Adult onset Niemann-Pick type C disease: A clinical, neuroimaging and molecular genetic study.

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Battisti, Carla; Tarugi, Patrizla; Dotti, Maria Teresa; De Stefano, Nicola; Vattimo, Angelo; Chierichetti, Francesea; Calandra, Sebastiano; Federico, Antonio

2003-11-01

We report on a patient with adult-onset Niemann-Pick type C (NPC) disease, carrying the mutations P1007 and I1061T in the NPC1 gene, presenting with marked psychiatric changes followed by dystonia and cognitive impairment. Filipin staining, single photon emission computed tomography perfusional, positron emission tomography metabolic, conventional magnetic resonance imaging, and magnetic resonance spectroscopy findings suggested a pathophysiological correlation with phenotype expression. This case expands the clinical and genetic spectrum of the rare adult-onset NPC disease phenotype.

Liver and Skin Histopathology in Adults with Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B)

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Thurberg, Beth L.; Wasserstein, Melissa P.; Schiano, Thomas; O’Brien, Fanny; Richards, Susan; Cox, Gerald F.; McGovern, Margaret M.

2012-01-01

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin in multiple cells types, and occurs most prominently within the liver, spleen and lungs, leading to significant clinical disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a Phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick disease type B. Eleven of the 17 were enrolled in the trial...

Peripheral neuropathy in type A Niemann-Pick disease. A morphological study.

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Landrieu, P; Saïd, G

1984-01-01

A black boy had a severe neuropathic form of Niemann-Pick disease (NPD) with a pronounced sphingomyelinase deficiency in the fibroblasts. Nerve conduction velocities were diminished, and a nerve biopsy was performed. Isolated fibers showed segmental demyelination and numerous dense bodies in the Schwann cells (SC). Electron microscopy revealed two categories of inclusions: the first was made up of lysosomal inclusions usually described in NPD. The second comprised myelin inclusions--sometimes still connected to the original myelin sheath--indicating severe myelinopathy. Both myelin debris and NPD inclusions were found in axoplasms and probably came from SC cytoplasm through axolemma lesions. NPD is a unique example of myelinopathy due to sphingomyelinase deficiency.

Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

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Sovan Sarkar

2013-12-01

Full Text Available Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1 disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.

Modeling Niemann Pick type C1 using human embryonic and induced pluripotent stem cells.

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Ordoñez, M Paulina; Steele, John W

2017-02-01

Data generated in Niemann Pick type C1 (NPC1) human embryonic and human induced pluripotent stem cell derived neurons complement on-going studies in animal models and provide the first example, in disease-relevant human cells, of processes that underlie preferential neuronal defects in a NPC1. Our work and that of other investigators in human neurons derived from stem cells highlight the importance of performing rigorous mechanistic studies in relevant cell types to guide drug discovery and therapeutic development, alongside of existing animal models. Through the use of human stem cell-derived models of disease, we can identify and discover or repurpose drugs that revert early events that lead to neuronal failure in NPC1. Together with the study of disease pathogenesis and efficacy of therapies in animal models, these strategies will fulfill the promise of stem cell technology in the development of new treatments for human diseases. This article is part of a Special Issue entitled SI: Exploiting human neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening

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Janine Reunert

2016-02-01

Full Text Available Niemann Pick type C (NP-C is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2 and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay.

Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann?Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report

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Cuisset, Jean-Marie; Sukno, S.; Trauffler, A.; Latour, P.; Dobbelaere, D.; Michaud, L.; Vall?e, L.

2016-01-01

Background Niemann?Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann?Pick disease type C, and has been used in that indication in Europe since 2010. Case pre...

Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease.

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Sarkar, Sovan; Carroll, Bernadette; Buganim, Yosef; Maetzel, Dorothea; Ng, Alex H M; Cassady, John P; Cohen, Malkiel A; Chakraborty, Souvik; Wang, Haoyi; Spooner, Eric; Ploegh, Hidde; Gsponer, Joerg; Korolchuk, Viktor I; Jaenisch, Rudolf

2013-12-12

Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Niemann-Pick disease type C

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Vanier Marie T

2010-06-01

Full Text Available Abstract Niemann-Pick C disease (NP-C is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood. The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period, gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period, and ataxia not unfrequently following initial psychiatric disturbances (adult form. The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype. Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential

Complex lipid trafficking in Niemann-Pick disease type C.

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Vanier, Marie T

2015-01-01

Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".

Distinct Niemann-Pick Disease Type C Clinical, Cytological, and Biochemical Phenotype in an Adult Patient With 1 Mutated, Overexpressed Allele

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Julia Jecel MD

2015-11-01

Full Text Available Niemann-Pick disease type C (NP-C is a rare autosomal-recessive neurovisceral lysosomal storage disease. We report on a juvenile onset, now 25-year-old female patient with typical neurologic symptoms, including vertical gaze palsy, of NP-C. The diagnosis was supported by a positive filipin test (“variant biochemical phenotype” of cholesterol accumulation in cultured fibroblasts, high numbers of “Niemann-Pick cells” in the bone marrow, and 1 positive out of 3 NP-C biomarkers tested, but NP-C was not definitely confirmed genetically. She showed only 1 known NPC1 variant (3 bp deletion in exon 18; p.N916del; this allele, however, being distinctly overexpressed at the messenger RNA level as compared to the wild-type allele, as a not as yet clarified (copathogenic? phenomenon. The patient’s mother, also carrying the p.N916del allele but without overexpression, has a chronic inflammatory disease of the central nervous system classified as multiple sclerosis. However, her severe clinical phenotype includes some signs also consistent with NP-C. The laboratory diagnosis of NP-C can be challenging in detecting novel disease constellations.

Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

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Mary Carmen Vázquez

2012-01-01

Full Text Available Niemann-Pick type C (NPC disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease.

Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease.

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Sarkar, Sovan; Maetzel, Dorothea; Korolchuk, Viktor I; Jaenisch, Rudolf

2014-06-01

Autophagy is essential for cellular homeostasis and its dysfunction in human diseases has been implicated in the accumulation of misfolded protein and in cellular toxicity. We have recently shown impairment in autophagic flux in the lipid storage disorder, Niemann-Pick type C1 (NPC1) disease associated with abnormal cholesterol sequestration, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery. Abrogation of autophagy also causes cholesterol accumulation, suggesting that defective autophagic flux in NPC1 disease may act as a primary causative factor not only by imparting its deleterious effects, but also by increasing cholesterol load. However, cholesterol depletion treatment with HP-β-cyclodextrin impedes autophagy, whereas pharmacologically stimulating autophagy restores its function independent of amphisome formation. Of potential therapeutic relevance is that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may rescue both the cholesterol and autophagy defects in NPC1 disease.

Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

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Ranganath, Prajnya; Matta, Divya; Bhavani, Gandham SriLakshmi; Wangnekar, Savita; Jain, Jamal Mohammed Nurul; Verma, Ishwar C; Kabra, Madhulika; Puri, Ratna Dua; Danda, Sumita; Gupta, Neerja; Girisha, Katta M; Sankar, Vaikom H; Patil, Siddaramappa J; Ramadevi, Akella Radha; Bhat, Meenakshi; Gowrishankar, Kalpana; Mandal, Kausik; Aggarwal, Shagun; Tamhankar, Parag Mohan; Tilak, Preetha; Phadke, Shubha R; Dalal, Ashwin

2016-10-01

Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Vestibular function in patients with Niemann-Pick type C disease.

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Bremova, Tatiana; Krafczyk, Siegbert; Bardins, Stanislavs; Reinke, Jörg; Strupp, Michael

2016-11-01

We investigated whether vestibular dysfunction may cause or contribute to postural imbalance and falls in patients with Niemann-Pick type C disease (NP-C). Eight patients with NP-C disease and 20 healthy controls were examined using the video-based head impulse test (vHIT) and caloric irrigation to investigate horizontal canal function as well as ocular- and cervical vestibular evoked myogenic potentials (o- and cVEMP), and binocular subjective visual vertical estimation (SVV) for otolith function, and static posturography. There were no significant differences in vestibulo-ocular gain, caloric excitability, o-/cVEMP measures or SVV between the two groups. Posturographic total sway path (tSP) and root mean square (RMS) were significantly higher in NP-C than in controls in 3 out of 4 conditions. The Romberg quotient (RQ) to assess the amount of visual stabilization was significantly lower in the NP-C than in the HC group. In contrast to other inherited metabolic disorders, such as Morbus Gaucher type 3, we did not find any evidence for an impairment of canal or otolith function in patients with NP-C as their cause of postural imbalance. Since RQ was low in NP-C patients, indicating proper sensory input, the observed increased postural sway is most likely due to a cerebellar dysfunction in NP-C, which may therefore, explain postural imbalance.

Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A [version 1; referees: 2 approved

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Priti G. Dalal

2015-12-01

Full Text Available A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anticipated difficult intubation and avoid post-operative ventilation.

Dietary cholesterol induces trafficking of intestinal Niemann-Pick Type C1 Like 1 from the brush border to endosomes

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Skov, Marianne; Tønnesen, Carina K; Hansen, Gert H

2011-01-01

The transmembrane protein Niemann-Pick C1 Like 1 (NPC1L1) belongs to the Niemann-Pick C1 (NPC1) family of cholesterol transporters and is mainly expressed in the liver and the small intestine. NPC1L1 is believed to be the main transporter responsible for the absorption of dietary cholesterol. Lik...

Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

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Manuel E. Lopez

2013-09-01

Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease.

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Domon, Magdalena; Nasir, Mehmet Nail; Matar, Gladys; Pikula, Slawomir; Besson, Françoise; Bandorowicz-Pikula, Joanna

2012-06-01

Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium and membrane-binding proteins have been recognized as cholesterol-interacting molecules and suggested to play a role in the formation, stabilization, and dynamics of membrane microdomains to affect membrane lateral organization and to attract other proteins and signaling molecules onto their territory. Furthermore, annexins were implicated in the interactions between cytosolic and membrane molecules, in the turnover and storage of cholesterol and in various signaling pathways. In this review, we focus on the mechanisms of interaction of annexins with lipid microdomains and the role of annexins in membrane microdomains dynamics including possible participation of the domain-associated forms of annexins in the etiology of human lysosomal storage disease called Niemann-Pick type C disease, related to the abnormal storage of cholesterol in the lysosome-like intracellular compartment. The involvement of annexins and cholesterol/sphingomyelin-enriched membrane microdomains in other pathologies including cardiac dysfunctions, neurodegenerative diseases, obesity, diabetes mellitus, and cancer is likely, but is not supported by substantial experimental observations, and therefore awaits further clarification.

Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology

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Kirkegaard, Thomas; Roth, Anke G; Petersen, Nikolaj H T

2010-01-01

Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization, a hallmark of stress-induced cell death. Clues to its molecular mechanism of action may lay in the recently...... reported stress- and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment. Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism......-is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds...

Olfactory deficits in Niemann-Pick type C1 (NPC1 disease.

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Marina Hovakimyan

Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/- to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE and olfactory bulb (OB. METHODOLOGY/PRINCIPAL FINDINGS: For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/- animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/- animals exhibit olfactory and trigeminal deficits. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-, which is accompanied by sensory deficits.

Probable Diagnosis of a Patient with Niemann-Pick Disease Type C: Managing Pitfalls of Exome Sequencing.

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Zeiger, William A; Jamal, Nasheed I; Scheuner, Maren T; Pittman, Patricia; Raymond, Kimiyo M; Morra, Massimo; Mishra, Shri K

2018-02-17

Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271.4, c.1554-1009G>A) and an additional heterozygous exonic variant of uncertain significance in the NPC1 gene (NM_000271.4, c.2524T>C). Follow-up biochemical testing was consistent with a diagnosis of probable Niemann-Pick disease Type C (NP-C). This case illustrates the potential of whole exome sequencing for diagnosing rare complex neurologic diseases. It also identifies several potential common pitfalls that must be navigated by clinicians when interpreting commercial whole exome sequencing results.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

OpenAIRE

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-01-01

2-Hydroxy-propyl-?-cyclodextrin (HP?CD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HP?CD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (e...

Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review

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Praveen K

2007-01-01

Full Text Available We present a report on an 18-year-old boy with Niemann-Pick disease Type C (NP-C who presented with progressive decline in scholastic performance since 9 years of age. At 12 years, he developed abnormal behavior and after 2 years had insidious onset, progressive gait ataxia and dysarthria followed by dystonia of the right upper extremity, excessive drooling, dysphagia and nasal regurgitation. He had coarse facies, depressed nasal bridge, high arched palate, crowded teeth, splenomegaly and peculiar facial grin. In addition, impaired vertical saccadic and pursuit eye movements, brisk muscle stretch reflexes and limb and gait ataxia were observed. He had a low IQ of 47 on Binet-Kamat test. The ultrasound examination of the abdomen confirmed the presence of moderate splenomegaly. Magnetic resonance imaging brain showed symmetrical leucoencephalopathy and mild cerebellar atrophy. Bone marrow aspiration showed numerous foamy macrophages and sea-blue histiocytes suggesting the diagnosis of NP-C.

Oculomotor abnormalities in children with Niemann-Pick type C.

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Blundell, James; Frisson, Steven; Chakrapani, Anupam; Gissen, Paul; Hendriksz, Chris; Vijay, Suresh; Olson, Andrew

2018-02-01

Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions. Copyright © 2017. Published by Elsevier Inc.

Changes in Caries Risk and Activity of a 9-Year-Old Patient with Niemann-Pick Disease Type C

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Késsia Suênia Fidelis Mesquita-Guimarães

2015-01-01

Full Text Available Objective. This case report describes the changes in caries risk and activity and dental treatment of a 9-year-old patient who presented with signs and symptoms of Niemann-Pick disease type C (NPC. Treatment. The preventive dental treatment included instructions to caregivers for oral hygiene and diet. A calcium hydroxide pulpotomy and restorative dental treatments were performed in a dental office with desensitization techniques and behavioral management. The patient was attended every 3 months for the control of dental plaque biofilm, for topical fluoride application, and for observing the pulpotomized tooth. Results. The bacterial plaque biofilm was being adequately controlled by the caregiver. After 2 years, the clinical and radiographic examination of the pulpotomized tooth showed the absence of internal root resorption and bone rarefaction, and clinical examination showed tooth sensitivity, dental pain, and gingival swelling. Conclusion. The pulpotomy prevented clinical and radiographic success. Dentists must be aware of and be able to identify systemic and local aspects associated with caries risk of children with NPC disease. Furthermore, dentists must employ stringent preventive measures and provide instructions to caregivers to reduce caries risk.

Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

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Movsesyan, Nina; Platt, Frances M.

2017-01-01

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID:29119141

Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.

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André R A Marques

Full Text Available Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC disease. In addition, glycosphingolipids (GSLs accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

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Hendriksz, Christian J; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Then Bergh, Florian; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A

2017-05-01

Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.

A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

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Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

2016-06-22

A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice.

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André R A Marques

Full Text Available The enzyme glucocerebrosidase (GBA hydrolyses glucosylceramide (GlcCer in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2. Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/- mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs, one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.

Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1

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Meghann W. Lau

2016-09-01

Full Text Available Niemann-Pick Disease, type C1 (NPC1 is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA and mean diffusivity (MD negatively correlate with NIH NPC neurological severity score (NNSS and motor severity subscores. Magnetic resonance imaging (MRI was obtained for thirty-nine NPC1 subjects, ages 1–21.9 years (mean = 11.1, SD = 6.1. Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

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Sandra Torres

2017-04-01

Full Text Available Niemann Pick type C (NPC disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE, but not N-acetylcysteine (NAC, restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

Treatment of cataplexy in Niemann-Pick disease type C with the use of miglustat.

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Zarowski, Marcin; Steinborn, Barbara; Gurda, Barbara; Dvorakova, Lenka; Vlaskova, Hana; Kothare, Sanjeev V

2011-01-01

Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann-Pick type C (NPC), Prader-Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher's disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent "drop attacks" while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Enfermedad de Niemann Pick tipo-A. Presentación de 12 casos

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Jorge Zarco-Román

2017-05-01

Full Text Available INTRODUCCIÓN: la enfermedad de Niemann Pick tipo A es una enfermedad hereditaria de depósito lisosomal, debida a un déficit de la enzima esfingomielinasa ácida, lo que da lugar a la acumulación de esfingomielina en las células del sistema reticuloendotelial y nervioso central. OBJETIVO: se describe el curso de la enfermedad de Niemann Pick tipo A en 12 pacientes: tres niños y nueve niñas, con edades entre 3 a 33 meses. MATERIAL Y MÉTODOS: estudio retrospectivo efectuado con base en la información de los expedientes de 12 pacientes, evaluados mediante un examen físico completo, oftalmológico, análisis de laboratorio, ultrasonido de abdomen, tomografía axial computarizada o resonancia magnética nuclear cerebral, radiografías de tórax, ecocardiograma, electroencefalograma, potenciales evocados auditivos y visuales, serie esofagogastroduodenal y serie ósea. Se obtuvo información sobre enfermedades intercurrentes y causas de muerte. RESULTADOS: la sintomatología comenzó en promedio a los 5.9 meses (2 a 16 meses y el diagnóstico definitivo se realizó a la edad de los 15.6 meses (3 a 33 meses a través del cuadro clínico sugestivo, con presencia de células espumosas en el aspirado de médula ósea 12/12 (100% y deficiencia de la enzima esfingomielinasa ácida en 12/12 pacientes (100%; la biopsia hepática fue sugestiva de enfermedad por atesoramiento en 5/12 (41.6%. Las manifestaciones clínicas por orden de frecuencia fueron: hepatoesplenomegalia y afección neurológica en 12/12 (100%, alteración pulmonar 11/12 (91.6%, hematológica 9/12 (80%, oftalmológica con mancha rojo cereza 9/12 (75%, ósea 6/12 (50%, y cardiaca 4/12 (33.3%. Únicamente hubo antecedente de consanguinidad en 4 familias (33.3%. CONCLUSIONES: el curso clínico de la enfermedad de Niemann Pick tipo A es muy similar entre los pacientes afectados, el primer dato clínico detectado es la hepatoesplenomegalia. Los pacientes están asintomáticos los primeros

Liver and Skin Histopathology in Adults with Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B)

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Thurberg, Beth L.; Wasserstein, Melissa P.; Schiano, Thomas; O’Brien, Fanny; Richards, Susan; Cox, Gerald F.; McGovern, Margaret M.

2012-01-01

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin in multiple cells types, and occurs most prominently within the liver, spleen and lungs, leading to significant clinical disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a Phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick disease type B. Eleven of the 17 were enrolled in the trial and each received a single dose of rhASM and underwent a repeat liver biopsy on Day 14. Biopsies were evaluated for fibrosis, sphingomyelin accumulation and macrophage infiltration by light and electron microscopy. When present, fibrosis was periportal and pericellular, predominantly surrounding affected Kupffer cells. Two baseline biopsies exhibited frank cirrhosis. Sphingomyelin was localized to isolated Kupffer cells in mildly affected biopsies and was present in both Kupffer cells and hepatocytes in more severely affected cases. Morphometric quantification of sphingomyelin storage in liver biopsies ranged from 4–44% of the microscopic field. Skin biopsies were also performed at baseline and Day 14 in order to compare the sphingomyelin distribution in a peripheral tissue to that of liver. Sphingomyelin storage was present at lower levels in multiple cell types of the skin, including dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells and Schwann cells. This Phase 1 trial of rhASM in adults with ASMD provided a unique opportunity for a prospective assessment of hepatic and skin pathology in this rare disease and their potential usage as pharmacodynamic biomarkers. PMID:22613999

Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

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Cristin D Davidson

2009-09-01

Full Text Available Niemann-Pick type C (NPC disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs. While current treatment therapies are limited, a few drugs tested in Npc1(-/- mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ and allopregnanolone, we noted increased lifespan for Npc1(-/- mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD, the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.Administration of CD to Npc1(-/- mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/- mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/- and Npc2(-/- mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

Mitochondrial G8292A and C8794T mutations in patients with Niemann-Pick disease type C.

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Masserrat, Abbas; Sharifpanah, Fatemeh; Akbari, Leila; Tonekaboni, Seyed Hasan; Karimzadeh, Parvaneh; Asharafi, Mahmood Reza; Mazouei, Safoura; Sauer, Heinrich; Houshmand, Massoud

2018-07-01

Niemann-Pick disease type C (NP-C) is a neurovisceral lipid storage disorder. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. NP-C is transmitted in an autosomal recessive manner and is caused by mutations in either the NPC1 (95% of families) or NPC2 gene. The estimated disease incidence is 1 in 120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. Variants of adenosine triphosphatase (ATPase) subunit 6 and ATPase subunit 8 ( ATPase6/8 ) in mitochondrial DNA (mtDNA) have been reported in different types of genetic diseases including NP-C. In the present study, the blood samples of 22 Iranian patients with NP-C and 150 healthy subjects as a control group were analyzed. The DNA of the blood samples was extracted by the salting out method and analyzed for ATPase6/8 mutations using polymerase chain reaction sequencing. Sequence variations in mitochondrial genome samples were determined via the Mitomap database. Analysis of sequencing data confirmed the existence of 11 different single nucleotide polymorphisms (SNPs) in patients with NP-C1. One of the most prevalent polymorphisms was the A8860G variant, which was observed in both affected and non-affected groups and determined to have no significant association with NP-C incidence. Amongst the 11 polymorphisms, only one was identified in the ATPase8 gene, while 9 including A8860G were observed in the ATPase6 gene. Furthermore, two SNPs, G8292A and C8792A, located in the non-coding region of mtDNA and the ATPase6 gene, respectively, exhibited significantly higher prevalence rates in NP-C1 patients compared with the control group (PC disease. In addition, the mitochondrial SNPs identified maybe pathogenic mutations involved in the development and prevalence of NP-C. Furthermore, these results suggest a higher occurrence of

Collaborative Development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease

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Ottinger, Elizabeth A.; Kao, Mark L.; Carrillo-Carrasco, Nuria; Yanjanin, Nicole; Shankar, Roopa Kanakatti; Janssen, Marjo; Brewster, Marcus; Scott, Ilona; Xu, Xin; Cradock, Jim; Terse, Pramod; Dehdashti, Seameen; Marugan, Juan; Zheng, Wei; Portilla, Lili; Hubbs, Alan; Pavan, William J.; Heiss, John; Vite, Charles H.; Walkley, Steven U.; Ory, Daniel S.; Silber, Steven A.; Porter, Forbes D.; Austin, Christopher P.; McKew, John C.

2014-01-01

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Science (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community. PMID:24283970

Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection.

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Gong, Xin; Qian, Hongwu; Zhou, Xinhui; Wu, Jianping; Wan, Tao; Cao, Pingping; Huang, Weiyun; Zhao, Xin; Wang, Xudong; Wang, Peiyi; Shi, Yi; Gao, George F; Zhou, Qiang; Yan, Nieng

2016-06-02

Niemann-Pick disease type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in the endosomal/lysosomal egress of low-density lipoprotein-derived cholesterol. NPC1 is also the intracellular receptor for Ebola virus (EBOV). Here, we present a 4.4 Å structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through the domain C. Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection. Copyright © 2016 Elsevier Inc. All rights reserved.

Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C

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Héron Bénédicte

2012-06-01

Full Text Available Abstract Background Niemann-Pick disease type C (NP-C is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Published data on the use of miglustat in paediatric patients in clinical practice settings are limited. We report findings from a prospective open-label study in the French paediatric NP-C cohort. Methods Data on all paediatric NP-C patients treated with miglustat in France between October 2006 and December 2010 were compiled. All patients had a confirmed diagnosis of NP-C, and received miglustat therapy according to manufacturer’s recommendations. Pre-treatment and follow-up assessments were conducted according to a standardized protocol. Results Twenty children were enrolled; 19 had NPC1 gene mutations and 1 had NPC2 gene mutations. The median age at diagnosis was 1.5 years, and the median age at miglustat initiation was 6.0 years. Eight NPC1 patients had the early-infantile, eight had the late-infantile, and three had the juvenile-onset forms of NP-C. A history of hepatosplenomegaly and/or other cholestatic symptoms was recorded in all 8 early-infantile onset patients, 3/8 late-infantile patients, and 1/3 juvenile onset patients. Brain imaging indicated white matter abnormalities in most patients. The median (range duration of miglustat therapy was 1.3 (0.6–2.3 years in early-infantile, 1.0 (0.8–5.0 year in late-infantile, and 1.0 (0.6–2.5 year in juvenile onset patients. NP-C disability scale scores indicated either stabilization or improvement of neurological manifestations in 1/8, 6/8, and 1/3 NPC1 patients in these subgroups, respectively. There were no correlations between brain imaging findings and disease course. Mild-to-moderate gastrointestinal disturbances were frequent during the first 3 months of miglustat therapy, but were easily managed with dietary modifications and/or anti-propulsive medication. Conclusions Miglustat can improve or stabilize neurological

Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

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Melanie Vincent

2010-09-01

Full Text Available Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease.Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown.Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.

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Lopez, Adam M; Jones, Ryan Dale; Repa, Joyce J; Turley, Stephen D

2018-06-07

Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase 1 (SOAT1) or sterol O-acyltransferase 2 (SOAT2) in various cell types, and lecithin cholesterol acyltransferase (LCAT) in plasma. Esterified cholesterol (EC) and triacylglycerol (TAG) contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase (LAL) within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C2 (NPC2) and Niemann-Pick C1 (NPC1), unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7 wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared to their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma ALT and AST activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

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Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A; Platt, Nick; Davis, Lianne C; Morgan, Anthony J; Höglinger, Doris; Tatituri, Raju Venkata V; Clark, Simon; Williams, Ian M; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S; Besra, Gurdyal S; Russell, David G; Brenner, Michael B; Sim, Edith; Platt, Frances M

2016-11-18

Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis , achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C [version 2; referees: 2 approved, 1 not approved

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Elena-Raluca Nicoli

2018-04-01

Full Text Available Niemann-Pick disease type C (NPC disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and also in post-mortem liver from NPC patients. We demonstrated the ability of the hydrophobic bile acid ursodeoxycholic acid (UDCA (3α, 7β-dihydroxy-5β-cholanic acid to correct the P450 system suppression. UDCA is used to treat several cholestatic disorders and was tested in NPC due to the P450 system being regulated by bile acids. Here, we compare the effect of UDCA and cholic acid (CA, another bile acid, in the NPC mouse model. We observed unexpected hepatotoxicity in response to CA treatment of NPC mice. No such hepatotoxicity was associated with UDCA treatment. These results suggest that CA treatment is contraindicated in NPC patients, whilst supporting the use of UDCA as an adjunctive therapy in NPC patients.

Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry.

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Bonnot, Olivier; Gama, Clarissa S; Mengel, Eugen; Pineda, Mercè; Vanier, Marie T; Watson, Louise; Watissée, Marie; Schwierin, Barbara; Patterson, Marc C

2017-10-09

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.

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Garnacho, Carmen; Dhami, Rajwinder; Simone, Eric; Dziubla, Thomas; Leferovich, John; Schuchman, Edward H; Muzykantov, Vladimir; Muro, Silvia

2008-05-01

Type B Niemann-Pick disease (NPD) is a multiorgan system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lung is an important and challenging therapeutic target. In this study, we designed and evaluated new delivery vehicles for enzyme replacement therapy of type B NPD, consisting of polystyrene and poly(lactic-coglycolic) acid polymer nanocarriers targeted to intercellular adhesion molecule (ICAM)-1, an endothelial surface protein up-regulated in many pathologies, including type B NPD. Real-time vascular imaging using intravital microscopy and postmortem imaging of mouse organs showed rapid, uniform, and efficient binding of fluorescently labeled ICAM-1-targeted ASM nanocarriers (anti-ICAM/ASM nanocarriers) to endothelium after i.v. injection in mice. Fluorescence microscopy of lung alveoli actin, tissue histology, and 125I-albumin blood-to-lung transport showed that anti-ICAM nanocarriers cause neither detectable lung injury, nor abnormal vascular permeability in animals. Radioisotope tracing showed rapid disappearance from the circulation and enhanced accumulation of anti-ICAM/125I-ASM nanocarriers over the nontargeted naked enzyme in kidney, heart, liver, spleen, and primarily lung, both in wild-type and ASM knockout mice. These data demonstrate that ICAM-1-targeted nanocarriers may enhance enzyme replacement therapy for type B NPD and perhaps other lysosomal storage disorders.

Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

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Hanna Alobaidy

2015-01-01

Full Text Available Niemann-Pick disease (NP-C is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy.

Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C.

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Lopez, Manuel E; Klein, Andrés D; Hong, Jennifer; Dimbil, Ubah J; Scott, Matthew P

2012-07-01

Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.

Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

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Jenny Shin

Full Text Available Niemann-Pick Disease, type C (NPC is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.

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Pablo J Sáez

Full Text Available Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻ showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.

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Sáez, Pablo J; Orellana, Juan A; Vega-Riveros, Natalia; Figueroa, Vania A; Hernández, Diego E; Castro, Juan F; Klein, Andrés D; Jiang, Jean X; Zanlungo, Silvana; Sáez, Juan C

2013-01-01

Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease.

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Tanaka, Yuta; Yamada, Yusei; Ishitsuka, Yoichi; Matsuo, Muneaki; Shiraishi, Koki; Wada, Koki; Uchio, Yushiro; Kondo, Yuki; Takeo, Toru; Nakagata, Naomi; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi; Mochinaga, Sakiko; Higaki, Katsumi; Ohno, Kousaku; Irie, Tetsumi

2015-01-01

Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1(-/-)) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000 mg/kg HPBCD improved the lifespan of Npc1(-/-) mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1(-/-) mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000 mg/kg), were approximately 1200-2500 µg/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1(-/-) mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1(-/-) mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.

Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

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Chan Chung

2016-05-01

Full Text Available Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1, promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.

Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability.

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Pontikis, Charles C; Davidson, Cristin D; Walkley, Steven U; Platt, Frances M; Begley, David J

2013-05-01

Niemann-Pick type C disease is an inherited autosomal recessive neurodegenerative disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-β-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113 ± 0.010 ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039 ± 0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilisation and clearance of cholesterol from the CNS.

Are Niemann-Pick type C proteins key players in cnidarian-dinoflagellate endosymbioses?

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Dani, Vincent; Ganot, Philippe; Priouzeau, Fabrice; Furla, Paola; Sabourault, Cecile

2014-09-01

The symbiotic interaction between cnidarians, such as corals and sea anemones, and the unicellular algae Symbiodinium is regulated by yet poorly understood cellular mechanisms, despite the ecological importance of coral reefs. These mechanisms, including host-symbiont recognition and metabolic exchange, control symbiosis stability under normal conditions, but also lead to symbiosis breakdown (bleaching) during stress. This study describes the repertoire of the sterol-trafficking proteins Niemann-Pick type C (NPC1 and NPC2) in the symbiotic sea anemone Anemonia viridis. We found one NPC1 gene in contrast to the two genes (NPC1 and NPC1L1) present in vertebrate genomes. While only one NPC2 gene is present in many metazoans, this gene has been duplicated in cnidarians, and we detected four NPC2 genes in A. viridis. However, only one gene (AvNPC2-d) was upregulated in symbiotic relative to aposymbiotic sea anemones and displayed higher expression in the gastrodermis (symbiont-containing tissue) than in the epidermis. We performed immunolabelling experiments on tentacle cross sections and demonstrated that the AvNPC2-d protein was closely associated with symbiosomes. In addition, AvNPC1 and AvNPC2-d gene expression was strongly downregulated during stress. These data suggest that AvNPC2-d is involved in both the stability and dysfunction of cnidarian-dinoflagellate symbioses. © 2014 John Wiley & Sons Ltd.

Pick disease

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Semantic dementia; Dementia - semantic; Frontotemporal dementia; FTD; Arnold Pick disease; 3R tauopathy ... doctors tell Pick disease apart from Alzheimer disease. (Memory loss is often the main, and earliest, symptom ...

Cholesterol pathways affected by small molecules that decrease sterol levels in Niemann-Pick type C mutant cells.

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Madalina Rujoi

2010-09-01

Full Text Available Niemann-Pick type C (NPC disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles.The effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds.Results herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155-1165.

Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.

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Wang, Han; Shi, Yi; Song, Jian; Qi, Jianxun; Lu, Guangwen; Yan, Jinghua; Gao, George F

2016-01-14

Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. Copyright © 2016 Elsevier Inc. All rights reserved.

Alteration of gene expression profile in Niemann-Pick type C mice correlates with tissue damage and oxidative stress.

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Mary C Vázquez

Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild-type control (Npc1(+/+; WT and homozygous-mutant (Npc1(-/-; NPC mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice. CONCLUSIONS/SIGNIFICANCE: In NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress

Cholesterol-dependent energy transfer between fluorescent proteins-insights into protein proximity of APP and BACE1 in different membranes in Niemann-Pick type C disease cells.

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von Einem, Bjoern; Weber, Petra; Wagner, Michael; Malnar, Martina; Kosicek, Marko; Hecimovic, Silva; Arnim, Christine A F von; Schneckenburger, Herbert

2012-11-26

Förster resonance energy transfer (FRET) -based techniques have recently been applied to study the interactions between β-site APP-cleaving enzyme-GFP (BACE1-GFP) and amyloid precursor protein-mRFP (APP-mRFP) in U373 glioblastoma cells. In this context, the role of APP-BACE1 proximity in Alzheimer's disease (AD) pathogenesis has been discussed. FRET was found to depend on intracellular cholesterol levels and associated alterations in membrane stiffness. Here, NPC1 null cells (CHO-NPC1-/-), exhibiting increased cholesterol levels and disturbed cholesterol transport similar to that observed in Niemann-Pick type C disease (NPC), were used to analyze the influence of altered cholesterol levels on APP-BACE1 proximity. Fluorescence lifetime measurements of whole CHO-wild type (WT) and CHO-NPC1-/- cells (EPI-illumination microscopy), as well as their plasma membranes (total internal reflection fluorescence microscopy, TIRFM), were performed. Additionally, generalized polarization (GP) measurements of CHO-WT and CHO-NPC1-/- cells incubated with the fluorescence marker laurdan were performed to determine membrane stiffness of plasma- and intracellular-membranes. CHO-NPC1-/- cells showed higher membrane stiffness at intracellular- but not plasma-membranes, equivalent to cholesterol accumulation in late endosomes/lysosomes. Along with higher membrane stiffness, the FRET efficiency between BACE1-GFP and APP-mRFP was reduced at intracellular membranes, but not within the plasma membrane of CHO-NPC1-/-. Our data show that FRET combined with TIRF is a powerful technique to determine protein proximity and membrane fluidity in cellular models of neurodegenerative diseases.

Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease.

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Subramanian, Kanagaraj; Rauniyar, Navin; Lavalleé-Adam, Mathieu; Yates, John R; Balch, William E

2017-11-01

Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (Ly) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. In this study, we performed comparative proteomic profiling of the response of NPC1 I1061T fibroblasts to Vorinostat. After stringent statistical criteria to filter identified proteins, we observed 202 proteins that are differentially expressed in Vorinostat-treated fibroblasts. These proteins are members of diverse cellular pathways including the endomembrane dependent protein folding-stability-degradation-trafficking axis, energy metabolism, and lipid metabolism. Our study shows that treatment of NPC1 I1061T fibroblasts with Vorinostat not only enhances pathways promoting the folding, stabilization and trafficking of NPC1 (I1061T) mutant to the LE/Ly, but alters the expression of lysosomal proteins, specifically the lysosomal acid lipase (LIPA) involved in the LIPA->NPC2->NPC1 based flow of cholesterol from the LE/Ly lumen to the LE/Ly membrane. We posit that the Vorinostat may modulate numerous pathways that operate in an integrated fashion through epigenetic and post-translational modifications reflecting acetylation/deacetylation balance to help manage the defective NPC1 fold, the function of the LE/Ly system and/or additional cholesterol metabolism/distribution pathways, that could globally contribute to improved mitigation of NPC1 disease in the clinic based on as yet uncharacterized principles of cellular metabolism dictating cholesterol homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

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Richard W D Welford

Full Text Available Niemann-Pick disease type C (NP-C is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC and glucosylsphingosine (GlcSph, appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection.

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Côté, Marceline; Misasi, John; Ren, Tao; Bruchez, Anna; Lee, Kyungae; Filone, Claire Marie; Hensley, Lisa; Li, Qi; Ory, Daniel; Chandran, Kartik; Cunningham, James

2011-08-24

Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that antiviral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the amino-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for antiviral therapy.

Lycopene reduces cholesterol absorption through the downregulation of Niemann-Pick C1-like 1 in Caco-2 cells.

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Zou, Jun; Feng, Dan

2015-11-01

Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Tomato lycopene has been found to have a hypocholesterolemic effect, and the effect was considered to be related to inhibition of cholesterol synthesis. However, since plasma cholesterol levels are also influenced by the absorption of cholesterol in the gut, the present study is to investigate whether lycopene affects cholesterol absorption in the intestinal Caco-2 cells. The Caco-2 cells were pretreated with lycopene at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and liver X receptor α (LXRα) was analyzed by Western blot and qPCR. We found that lycopene dose dependently inhibited cholesterol absorption and the expression of NPC1L1 protein and NPC1L1 mRNA. The inhibitory effects of lycopene on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the LXRα pathway. This study provides the first evidence that lycopene inhibits cholesterol absorption in the intestinal cells and this inhibitory effect of lycopene is mediated, at least in part, by LXRα-NPC1L1 signaling pathway. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Protein replacement therapy partially corrects the cholesterol-storage phenotype in a mouse model of Niemann-Pick type C2 disease.

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Gitte Krogh Nielsen

Full Text Available Niemann-Pick type C2 (NPC2 disease is a fatal autosomal recessive neurovisceral degenerative disorder characterized by late endosomal-lysosomal sequestration of low-density lipoprotein derived cholesterol. The breach in intracellular cholesterol homeostasis is caused by deficiency of functional NPC2, a soluble sterol binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. As currently there is no effective treatment for the disorder, we have investigated the efficacy of NPC2 replacement therapy in a murine gene-trap model of NPC2-disease generated on the 129P2/OlaHsd genetic background. NPC2 was purified from bovine milk and its functional competence assured in NPC2-deficient fibroblasts using the specific cholesterol fluorescent probe filipin. For evaluation of phenotype correction in vivo, three-week-old NPC2(-/- mice received two weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. Whereas the saline treated NPC2(-/- mice exhibited massive visceral cholesterol storage as compared to their wild-type littermates, administration of NPC2 caused a marked reduction in cholesterol build up. The histological findings, indicating an amelioration of the disease pathology in liver, spleen, and lungs, corroborated the biochemical results. Little or no difference in the overall cholesterol levels was observed in the kidneys, blood, cerebral cortex and hippocampus when comparing NPC2(-/- and wild type mice. However, cerebellum cholesterol was increased about two fold in NPC2(-/- mice compared with wild-type littermates. Weight gain performance was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Accordingly, ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2(-/- animals 87 days post partum. Our data indicate that protein replacement may be a beneficial therapeutic approach in the

Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells

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Dorothea Maetzel

2014-06-01

Full Text Available Niemann-Pick type C (NPC disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs using transcription activator-like effector nucleases (TALENs. We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

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Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; Duross, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-08-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1-/-) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1-/- cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

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Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-01-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.

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Stephanie M Marshall

Full Text Available An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL support TICE, antisense oligonucleotides (ASO were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP, which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg mice, which predominantly excrete cholesterol via TICE, and wild type (WT littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.

Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat.

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Munkacsi, Andrew B; Hammond, Natalie; Schneider, Remy T; Senanayake, Dinindu S; Higaki, Katsumi; Lagutin, Kirill; Bloor, Stephen J; Ory, Daniel S; Maue, Robert A; Chen, Fannie W; Hernandez-Ono, Antonio; Dahlson, Nicole; Repa, Joyce J; Ginsberg, Henry N; Ioannou, Yiannis A; Sturley, Stephen L

2017-03-17

Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1 nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null ( Npc1 -/- ) and missense ( Npc1 nmf164 ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat*

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Munkacsi, Andrew B.; Hammond, Natalie; Schneider, Remy T.; Senanayake, Dinindu S.; Higaki, Katsumi; Lagutin, Kirill; Bloor, Stephen J.; Ory, Daniel S.; Maue, Robert A.; Chen, Fannie W.; Hernandez-Ono, Antonio; Dahlson, Nicole; Repa, Joyce J.; Ginsberg, Henry N.; Ioannou, Yiannis A.; Sturley, Stephen L.

2017-01-01

Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1−/−) and missense (Npc1nmf164) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. PMID:28031458

Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts

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Kosicek, Marko; Malnar, Martina; Goate, Alison; Hecimovic, Silva

2010-01-01

It has been suggested that cholesterol may modulate amyloid-β (Aβ) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD (β-amyloid precursor protein (APP), β-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/Aβ formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1 -/- cells (NPC cells) and parental CHOwt cells. By sucrose density gradient centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, γ-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards Aβ occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes.

Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.

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Karten, Barbara; Vance, Dennis E; Campenot, Robert B; Vance, Jean E

2003-02-07

Niemann Pick type C (NPC) disease is a progressive neurodegenerative disorder. In cells lacking functional NPC1 protein, endocytosed cholesterol accumulates in late endosomes/lysosomes. We utilized primary neuronal cultures in which cell bodies and distal axons reside in separate compartments to investigate the requirement of NPC1 protein for transport of cholesterol from cell bodies to distal axons. We have recently observed that in NPC1-deficient neurons compared with wild-type neurons, cholesterol accumulates in cell bodies but is reduced in distal axons (Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neurochem. 83, 1154-1163). We now show that NPC1 protein is expressed in both cell bodies and distal axons. In NPC1-deficient neurons, cholesterol delivered to cell bodies from low density lipoproteins (LDLs), high density lipoproteins, or cyclodextrin complexes was transported into axons in normal amounts, whereas transport of endogenously synthesized cholesterol was impaired. Inhibition of cholesterol synthesis with pravastatin in wild-type and NPC1-deficient neurons reduced axonal growth. However, LDLs restored a normal rate of growth to wild-type but not NPC1-deficient neurons treated with pravastatin. Thus, although LDL cholesterol is transported into axons of NPC1-deficient neurons, this source of cholesterol does not sustain normal axonal growth. Over the lifespan of NPC1-deficient neurons, these defects in cholesterol transport might be responsible for the observed altered distribution of cholesterol between cell bodies and axons and, consequently, might contribute to the neurological dysfunction in NPC disease.

Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis.

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Millard, E E; Srivastava, K; Traub, L M; Schaffer, J E; Ory, D S

2000-12-08

The Niemann-Pick type C1 (NPC1) protein is a key participant in intracellular trafficking of low density lipoprotein cholesterol, but its role in regulation of sterol homeostasis is not well understood. To characterize further the function of NPC1, we generated stable Chinese hamster ovary (CHO) cell lines overexpressing the human NPC1 protein (CHO/NPC1). NPC1 overexpression increases the rate of trafficking of low density lipoprotein cholesterol to the endoplasmic reticulum and the rate of delivery of endosomal cholesterol to the plasma membrane (PM). CHO/NPC1 cells exhibit a 1.5-fold increase in total cellular cholesterol and up to a 2.9-fold increase in PM cholesterol. This increase in PM cholesterol is closely paralleled by a 3-fold increase in de novo cholesterol synthesis. Inhibition of cholesterol synthesis results in marked redistribution of PM cholesterol to intracellular sites, suggesting an unsuspected role for NPC1 in internalization of PM cholesterol. Despite elevated total cellular cholesterol, CHO/NPC1 cells exhibit increased cholesterol synthesis, which may be attributable to both resistance to oxysterol suppression of sterol-regulated gene expression and to reduced endoplasmic reticulum cholesterol levels under basal conditions. Taken together, these studies provide important new insights into the role of NPC1 in the determination of the levels and distribution of cellular cholesterol.

Intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts

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Liscum, L.; Ruggiero, R.M.; Faust, J.R.

1989-01-01

Niemann-Pick disease type C (NPC) is characterized by substantial intracellular accumulation of unesterified cholesterol. The accumulation of unesterified cholesterol in NPC fibroblasts cultured with low density lipoprotein (LDL) appears to result from the inability of LDL to stimulate cholesterol esterification in addition to impaired LDL-mediated downregulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in cholesterol transport in NPC cells has been inferred from previous studies, no experiments have been reported that measure the intracellular movement of LDL-cholesterol specifically. We have used four approaches to assess intracellular cholesterol transport in normal and NPC cells and have determined the following: (a) mevinolin-inhibited NPC cells are defective in using LDL-cholesterol for growth. However, exogenously added mevalonate restores cell growth equally in normal and NPC cells; (b) the transport of LDL-derived [3H]cholesterol to the plasma membrane is slower in NPC cells, while the rate of appearance of [3H]acetate-derived, endogenously synthesized [3H]cholesterol at the plasma membrane is the same for normal and NPC cells; (c) in NPC cells, LDL-derived [3H]cholesterol accumulates in lysosomes to higher levels than normal, resulting in defective movement to other cell membranes; and (d) incubation of cells with LDL causes an increase in cholesterol content of NPC lysosomes that is threefold greater than that observed in normal lysosomes. Our results indicate that a cholesterol transport defect exists in NPC that is specific for LDL-derived cholesterol

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice.

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Schlegel, Victoria; Thieme, Markus; Holzmann, Carsten; Witt, Martin; Grittner, Ulrike; Rolfs, Arndt; Wree, Andreas

2016-11-09

Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1 nih Npc1 -/- mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1 -/- animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

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Victoria Schlegel

2016-11-01

Full Text Available Niemann-Pick Type C1 (NPC1 is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine

International Nuclear Information System (INIS)

Duval, Caroline; Touche, Veronique; Tailleux, Anne; Fruchart, Jean-Charles; Fievet, Catherine; Clavey, Veronique; Staels, Bart; Lestavel, Sophie

2006-01-01

Niemann-Pick C1 like 1 (NPC1L1) is a protein critical for intestinal cholesterol absorption. The nuclear receptors peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRα and LXRβ) are major regulators of cholesterol homeostasis and their activation results in a reduced absorption of intestinal cholesterol. The goal of this study was to define the role of PPARα and LXR nuclear receptors in the regulation of NPC1L1 gene expression. We show that LXR activators down-regulate NPC1L1 mRNA levels in the human enterocyte cell line Caco-2/TC7, whereas PPARα ligands have no effect. Furthermore, NPC1L1 mRNA levels are decreased in vivo, in duodenum of mice treated with the LXR agonist T0901317. In conclusion, the present study identifies NPC1L1 as a novel LXR target gene further supporting a crucial role of LXR in intestinal cholesterol homeostasis

Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.

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Koens, L H; Kuiper, A; Coenen, M A; Elting, J W J; de Vries, J J; Engelen, M; Koelman, J H T M; van Spronsen, F J; Spikman, J M; de Koning, T J; Tijssen, M A J

2016-09-01

Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus. Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed. A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities. Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin

Niemann-Pick C1 (NPC1/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor

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Esther Ndungo

2012-10-01

Full Text Available We recently demonstrated that Niemann-Pick C1 (NPC1, a ubiquitous 13-pass cellular membrane protein involved in lysosomal cholesterol transport, is a critical entry receptor for filoviruses. Here we show that Niemann-Pick C1-like1 (NPC1L1, an NPC1 paralog and hepatitis C virus entry factor, lacks filovirus receptor activity. We exploited the structural similarity between NPC1 and NPC1L1 to construct and analyze a panel of chimeras in which NPC1L1 sequences were replaced with cognate sequences from NPC1. Only one chimera, NPC1L1 containing the second luminal domain (C of NPC1 in place of its own, bound to the viral glycoprotein, GP. This engineered protein mediated authentic filovirus infection nearly as well as wild-type NPC1, and more efficiently than did a minimal NPC1 domain C-based receptor recently described by us. A reciprocal chimera, NPC1 containing NPC1L1’s domain C, was completely inactive. Remarkably, an intra-domain NPC1L1-NPC1 chimera bearing only a ~130-amino acid N–terminal region of NPC1 domain C could confer substantial viral receptor activity on NPC1L1. Taken together, these findings account for the failure of NPC1L1 to serve as a filovirus receptor, highlight the central role of the luminal domain C of NPC1 in filovirus entry, and reveal the direct involvement of N–terminal domain C sequences in NPC1’s function as a filovirus receptor.

Lysosomal pH-inducible supramolecular dissociation of polyrotaxanes possessing acid-labile N-triphenylmethyl end groups and their therapeutic potential for Niemann-Pick type C disease

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Tamura, Atsushi; Nishida, Kei; Yui, Nobuhiko

2016-01-01

Niemann-Pick type C (NPC) disease is characterized by the accumulation of cholesterol in lysosomes. We have previously reported that biocleavable polyrotaxanes (PRXs) composed of β-cyclodextrins (β-CDs) threaded onto a linear polymer capped with bulky stopper molecules via intracellularly cleavable linkers show remarkable cholesterol reducing effects in NPC disease patient-derived fibroblasts owing to the stimuli-responsive intracellular dissociation of PRXs and subsequent β-CD release from the PRXs. Herein, we describe a series of novel acid-labile 2-(2-hydroxyethoxy)ethyl group-modified PRXs (HEE-PRXs) bearing terminal N-triphenylmethyl (N-Trt) groups as a cleavable component for the treatment of NPC disease. The N-Trt end groups of the HEE-PRXs underwent acidic pH-induced cleavage and led to the dissociation of their supramolecular structure. A kinetic study revealed that the number of HEE groups on the PRX did not affect the cleavage kinetics of the N-Trt end groups of the HEE-PRXs. The effect of the number of HEE groups of the HEE-PRXs, which was modified to impart water solubility to the PRXs, on cellular internalization efficiency, lysosomal localization efficiency, and cholesterol reduction ability in NPC disease-derived fibroblasts (NPC1 fibroblasts) was also investigated. The cellular uptake and lysosomal localization efficiency were almost equivalent for HEE-PRXs with different numbers of HEE groups. However, the cholesterol reducing ability of the HEE-PRXs in NPC1 fibroblasts was affected by the number of HEE groups, and HEE-PRXs with a high number of HEE groups were unable to reduce lysosomal cholesterol accumulation. This deficiency is most likely due to the cholesterol-solubilizing ability of HEE-modified β-CDs released from the HEE-PRXs. We conclude that the N-Trt group acts as a cleavable component to induce the lysosomal dissociation of HEE-PRXs, and acid-labile HEE-PRXs with an optimal number of HEE groups (4.1 to 5.4 HEE groups per single �

Quantitative comparison of the efficacy of various compounds in lowering intracellular cholesterol levels in Niemann-Pick type C fibroblasts.

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Zachary T Wehrmann

Full Text Available Niemann-Pick Type C disease (NPC is a lethal, autosomal recessive disorder caused by mutations in the NPC1 and NPC2 cholesterol transport proteins. NPC's hallmark symptoms include an accumulation of unesterified cholesterol and other lipids in the late endosomal and lysosomal cellular compartments, causing progressive neurodegeneration and death. Although the age of onset may vary in those affected, NPC most often manifests in juveniles, and is usually fatal before adolescence. In this study, we investigated the effects of various drugs, many of which modify the epigenetic control of NPC1/NPC2 gene expression, in lowering the otherwise harmful elevated intracellular cholesterol levels in NPC cells. Our studies utilized a previously described image analysis technique, which allowed us to make quantitative comparisons of the efficacy of these drugs in lowering cholesterol levels in a common NPC1 mutant model. Of the drugs analyzed, several that have been previously studied (vorinostat, panobinostat, and β-cyclodextrin significantly lowered the relative amount of unesterified cellular cholesterol, consistent with earlier observations. In addition, a novel potential treatment, rapamycin, likewise alleviated the NPC phenotype. We also studied combinations of effective compounds with β-cyclodextrin; the addition of β-cyclodextrin significantly enhanced the cholesterol-lowering activity of vorinostat and panobinostat, but had mixed effects with rapamycin. Collectively, these results may provide a basis for the eventual development of improved NPC therapies.

Seven novel mutations of the SMPD1 gene in four Chinese patients with Niemann-Pick disease type A and prenatal diagnosis for four fetuses.

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Ding, Yuan; Li, Xiyuan; Liu, Yupeng; Hua, Ying; Song, Jinqing; Wang, Liwen; Li, Mengqiu; Qin, Yaping; Yang, Yanling

2016-04-01

Niemann-Pick disease type A (NPD-A) is a rare autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency. Only a few cases have been documented in mainland China, and prenatal diagnosis has not been performed to date. In this study, the clinical and laboratory features of four Chinese patients with early-onset NPD-A were summarized. Four patients with NPD-A were the firstborns of non-consanguineous parents from four unrelated Chinese families. Bone marrow analysis, acid sphingomyelinase assay and genetic studies were performed. SMPD1 gene studies on amniocytes were performed for the prenatal diagnosis of four fetuses from three families. Four patients were admitted at the age of 1-10 months due to jaundice, hepatosplenomegaly and psychomotor retardation. Liver histopathological analysis revealed glucolipid accumulation. Massive foamy histiocytes were found in the bone marrow. Acid sphingomyelinase activities of peripheral blood leukocytes were significantly decreased (4.05-21.9 nmol/h/mg protein, normal range 216.1-950.9 nmol/h/mg protein). Seven novel mutations (c.518-519insT, c.562_563insC, c.792Gdel, c.949G>A, c.1487_1499delACCGTGTGTACCA, c.1495T>C and c.1670T>C) of the SMPD1 gene were identified in four patients. Only one fetus had two mutations of the SMPD1 gene of amniocytes. The results suggested that the fetus was affected by NPD-A. The mother chose artificial abortion. The other three fetuses were not affected by NPD-A. No mutation of the SMPD1 gene was detected in the cultured amniocytes from the mothers. Postnatal genetic analysis and normal development of the three infants confirmed the prenatal diagnosis. Seven novel mutations associated with NPD-A were identified in the Chinese population. Prenatal diagnosis for four fetuses of three families was successfully performed by amniocyte gene analysis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synthesis, characterization, and evaluation of pluronic-based β-cyclodextrin polyrotaxanes for mobilization of accumulated cholesterol from Niemann-Pick type C fibroblasts.

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Collins, Christopher J; McCauliff, Leslie A; Hyun, Seok-Hee; Zhang, Zhaorui; Paul, Lake N; Kulkarni, Aditya; Zick, Klaus; Wirth, Mary; Storch, Judith; Thompson, David H

2013-05-14

Several lines of evidence suggest that β-cyclodextrin (β-CD) derivatives initiate the efflux of accumulated, unesterified cholesterol from the late endosomal/lysosomal compartment in Niemann Pick C (NPC) disease models. Unfortunately, repeated injections or continuous infusions of current β-CD therapies are required to sustain suppression of symptoms and prolong life. In an effort to make CD treatment a more viable option by boosting efficacy and improving pharmacokinetics, a library of Pluronic surfactant-based β-CD polyrotaxanes has been developed using biocompatible poly(ethylene glycol) (PEG)-polypropylene glycol (PPG)-PEG triblock copolymers. These compounds carry multiple copies of β-CD as shown by (1)H NMR, 2D nuclear Overhouser effect spectroscopy, gel permeation chromatography/multiangle light scattering, analytical ultracentrifugation analysis, matrix assisted laser desorption/ionization mass spectrometry, and diffusion-ordered spectroscopy. Analyses of free β-cyclodextrin contamination in the compounds were made by reverse phase high pressure liquid chromatography and hydrophilic interaction liquid chromatography. Dethreading kinetics were studied by reverse phase high pressure liquid chromatography, UV/vis, and (1)H NMR analysis. Filipin staining studies using npc2(-/-) fibroblasts show significant reversal of cholesterol accumulation after treatment with polyrotaxane compounds. The rate and efficacy of reversal is similar to that achieved by equivalent amounts of monomeric β-CD alone.

Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

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Antoneta Granic

Full Text Available Elevated low-density lipoprotein (LDL-cholesterol is a risk factor for both Alzheimer's disease (AD and Atherosclerosis (CVD, suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1 high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2 Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3 oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL, induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4 LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5 cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6 ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

A new simple and rapid LC-ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann-Pick type C disease.

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Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Martinelli, Diego; Verrigni, Daniela; Carrozzo, Rosalba; Bertini, Enrico; Pastore, Anna; Dionisi-Vici, Carlo; Johnson, David W

2014-11-01

Two oxysterols, cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC), have been recently proposed as diagnostic markers of Niemann-Pick type C (NP-C) disease, representing a potential alternative diagnostic tool to the more invasive and time consuming filipin test in cultured fibroblasts. Usually, the oxysterols are detected and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using atmospheric pressure chemical ionization (APCI) or electro-spray-ionization (ESI) sources, after a variety of derivatization procedures to enhance sensitivity. We developed a sensitive LC-MS/MS method to quantify the oxysterols in plasma as dimethylaminobutyrate ester, suitable for ESI analysis. This method, with an easy liquid-phase extraction and a short derivatization procedure, has been validated to demonstrate specificity, linearity, recovery, lowest limit of quantification, accuracy and precision. The assay was linear over a concentration range of 0.5-200ng/mL for C-triol and 1.0-200ng/mL for 7-KC. Intra-day and inter-day coefficients of variation (CV%) were <15% for both metabolites. Receiver operating characteristic analysis estimates that the area under curve was 0.998 for C-triol, and 0.972 for 7-KC, implying a significant discriminatory power for the method in this patient population of both oxysterols. In summary, our method provides a simple, rapid and non-invasive diagnostic tool for the biochemical diagnosis of NP-C disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein.

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Mahua Maulik

Full Text Available Niemann-Pick type C (NPC disease, a rare autosomal recessive disorder caused mostly by mutation in NPC1 gene, is pathologically characterized by the accumulation of free cholesterol in brain and other tissues. This is accompanied by gliosis and loss of neurons in selected brain regions, including the cerebellum. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease, including the presence of neurofibrillary tangles and increased levels of amyloid precursor protein (APP-derived β-amyloid (Aβ peptides in vulnerable brain neurons. To evaluate the role of Aβ in NPC disease, we determined the gene expression profile in selected brain regions of our recently developed bigenic ANPC mice, generated by crossing APP transgenic (Tg mice with heterozygous Npc1-deficient mice. The ANPC mice exhibited exacerbated neuronal and glial pathology compared to other genotypes [i.e., APP-Tg, double heterozygous (Dhet, Npc1-null and wild-type mice]. Analysis of expression profiles of 86 selected genes using real-time RT-PCR arrays showed a wide-spectrum of alterations in the four genotypes compared to wild-type controls. The changes observed in APP-Tg and Dhet mice are limited to only few genes involved mostly in the regulation of cholesterol metabolism, whereas Npc1-null and ANPC mice showed alterations in the expression profiles of a number of genes regulating cholesterol homeostasis, APP metabolism, vesicular trafficking and cell death mechanism in both hippocampus and cerebellum compared to wild-type mice. Intriguingly, ANPC and Npc1-null mice, with some exceptions, exhibited similar changes, although more genes were differentially expressed in the affected cerebellum than the relatively spared hippocampus. The altered gene profiles were found to match with the corresponding protein levels. These results suggest that lack of Npc1 protein can alter the expression profile of selected transcripts as well as proteins, and

Neuroimaging Findings in a Brain With Niemann–Pick Type C Disease

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Jei-Yie Huang

2011-08-01

Full Text Available Niemann-Pick type C disease (NPC is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low-density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI, magnetic resonance spectrography (MRS and 18-fluoro-2-deoxyglucose positron emission tomography (PET imaging results for a 22-year-old male NPC patient. The patient's two MRI studies (at age 19 years and 22 years demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal-occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway [version 1; referees: 2 approved, 1 approved with reservations

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Paul Fineran

2016-11-01

Full Text Available Background. Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC, a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. Methods. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Results. Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway [version 2; referees: 2 approved, 2 approved with reservations

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Paul Fineran

2017-06-01

Full Text Available Background. Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with intracellular mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC, a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC.  Methods. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed.  Results. Macrophages infected with intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in

Loss of Niemann-Pick C1 or C2 protein results in similar biochemical changes suggesting that these proteins function in a common lysosomal pathway.

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Sayali S Dixit

Full Text Available Niemann-Pick Type C (NPC disease is a lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids in the endolysosomal system. NPC disease results from a defect in either of two distinct cholesterol-binding proteins: a transmembrane protein, NPC1, and a small soluble protein, NPC2. NPC1 and NPC2 are thought to function closely in the export of lysosomal cholesterol with both proteins binding cholesterol in vitro but they may have unrelated lysosomal roles. To investigate this possibility, we compared biochemical consequences of the loss of either protein. Analyses of lysosome-enriched subcellular fractions from brain and liver revealed similar decreases in buoyant densities of lysosomes from NPC1 or NPC2 deficient mice compared to controls. The subcellular distribution of both proteins was similar and paralleled a lysosomal marker. In liver, absence of either NPC1 or NPC2 resulted in similar alterations in the carbohydrate processing of the lysosomal protease, tripeptidyl peptidase I. These results highlight biochemical alterations in the lysosomal system of the NPC-mutant mice that appear secondary to lipid storage. In addition, the similarity in biochemical phenotypes resulting from either NPC1 or NPC2 deficiency supports models in which the function of these two proteins within lysosomes are linked closely.

Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.

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Barry E Kennedy

Full Text Available Niemann-Pick Type C (NPC disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 (-/- mice at pre-symptomatic, early symptomatic and late stage disease by (1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 (-/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 (-/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.

Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

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Sainz, Bruno; Barretto, Naina; Martin, Danyelle N.; Hiraga, Nobuhiko; Imamura, Michio; Hussain, Snawar; Marsh, Katherine A.; Yu, Xuemei; Chayama, Kazuaki; Alrefai, Waddah A.; Uprichard, Susan L.

2011-01-01

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ~170 million individuals infected and current interferon-based treatment having toxic side-effects and marginal efficacy, more effective antivirals are critically needed1. Although HCV protease inhibitors were just FDA approved, analogous to HIV therapy, optimal HCV therapy likely will require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a promising multi-faceted target for antiviral intervention; however, to date FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-Like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection as silencing or antibody-mediated blocking of NPC1L1 impairs cell-cultured-derived HCV (HCVcc) infection initiation. In addition, the clinically-available FDA-approved NPC1L1 antagonist ezetimibe2,3 potently blocks HCV uptake in vitro via a virion cholesterol-dependent step prior to virion-cell membrane fusion. Importantly, ezetimibe inhibits infection of all major HCV genotypes in vitro, and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor, but also discovered a new antiviral target and potential therapeutic agent. PMID:22231557

Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1.

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Park, Walter D; O'Brien, John F; Lundquist, Patrick A; Kraft, Daniel L; Vockley, Cate Walsh; Karnes, Pamela S; Patterson, Marc C; Snow, Karen

2003-10-01

The two known complementation groups of Niemann-Pick Type C disease, NPC1 and NPC2, result from non-allelic protein defects. Both the NPC1 and NPC2 (HE1) gene products are intimately involved in cholesterol and glycolipid trafficking and/or transport. We describe mutation analysis on samples from 143 unrelated affected NPC patients using conformation sensitive gel electrophoresis and DNA sequencing as the primary mutation screening methods for NPC1 and NPC2, respectively. These methods are robust, sensitive, and do not require any specialized laboratory equipment. Analyses identified two NPC1 mutations for 115 (80.4%) patients, one NPC1 mutation for 10 (7.0%) patients, two NPC2 mutations for five (3.5%) patients, one NPC2 mutation for one (0.7%) patient, and no mutations for 12 (8.4%) patients. Thus, mutations were identified on 251 of 286 (88%) disease alleles, including 121 different mutations (114 in NPC1 and seven in NPC2), 58 of which are previously unreported. The most common NPC1 mutation, I1061T, was detected on 18% of NPC alleles. Other NPC1 mutations were mostly private, missense mutations located throughout the gene with clustering in the cysteine-rich luminal domain. Correlation with biochemical data suggests classification of several mutations as severe and others as moderate or variable. The region between amino acids 1038 and 1253, which shares 35% identity with Patched 1, appears to be a hot spot for mutations. Additionally, a high percentage of mutations were located at amino acids identical to the NPC1 homolog, NPC1L1. Biochemical complementation analysis of cases negative for mutations revealed a high percentage of equivocal results where the complementation group appeared to be non-NPC1 and non-NPC2. This raises the possibilities of an additional NPC complementation group(s) or non-specificity of the biochemical testing for NPC. These caveats must be considered when offering mutation testing as a clinical service. Copyright 2003 Wiley-Liss, Inc.

Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection.

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Charles J Shoemaker

Full Text Available Ebola virus (EBOV is an enveloped RNA virus that causes hemorrhagic fever in humans and non-human primates. Infection requires internalization from the cell surface and trafficking to a late endocytic compartment, where viral fusion occurs, providing a conduit for the viral genome to enter the cytoplasm and initiate replication. In a concurrent study, we identified clomiphene as a potent inhibitor of EBOV entry. Here, we screened eleven inhibitors that target the same biosynthetic pathway as clomiphene. From this screen we identified six compounds, including U18666A, that block EBOV infection (IC(50 1.6 to 8.0 µM at a late stage of entry. Intriguingly, all six are cationic amphiphiles that share additional chemical features. U18666A induces phenotypes, including cholesterol accumulation in endosomes, associated with defects in Niemann-Pick C1 protein (NPC1, a late endosomal and lysosomal protein required for EBOV entry. We tested and found that all six EBOV entry inhibitors from our screen induced cholesterol accumulation. We further showed that higher concentrations of cationic amphiphiles are required to inhibit EBOV entry into cells that overexpress NPC1 than parental cells, supporting the contention that they inhibit EBOV entry in an NPC1-dependent manner. A previously reported inhibitor, compound 3.47, inhibits EBOV entry by blocking binding of the EBOV glycoprotein to NPC1. None of the cationic amphiphiles tested had this effect. Hence, multiple cationic amphiphiles (including several FDA approved agents inhibit EBOV entry in an NPC1-dependent fashion, but by a mechanism distinct from that of compound 3.47. Our findings suggest that there are minimally two ways of perturbing NPC1-dependent pathways that can block EBOV entry, increasing the attractiveness of NPC1 as an anti-filoviral therapeutic target.

Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients.

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Hammerschmidt, Tatiane Grazieli; de Oliveira Schmitt Ribas, Graziela; Saraiva-Pereira, Maria Luiza; Bonatto, Márcia Polese; Kessler, Rejane Gus; Souza, Fernanda Timm Seabra; Trapp, Franciele; Michelin-Tirelli, Kristiane; Burin, Maira Graeff; Giugliani, Roberto; Vargas, Carmen Regla

2018-05-01

Niemann-Pick type C (NP-C), one of 50 inherited lysosomal storage disorders, is caused by NPC protein impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. The clinical manifestations of NP-C include hepatosplenomegaly, neurological and psychiatric symptoms. Current diagnosis for NP-C is based on observation of the accumulated cholesterol in fibroblasts of affected individuals, using an invasive and time expensive test, called Filipin staining. Lately, two metabolites that are markedly increased in NP-C patients are arising as biomarkers for this disease screening: 7-ketocholesterol and cholestane-3β,5α,6β-triol, both oxidized cholesterol products. In this work, we aimed to evaluate the performance of cholestane-3β,5α,6β-triol analysis for the screening and monitoring of NPC patients, correlating it with chitotriosidase levels, Filipin staining and molecular analysis. It was investigated 76 non-treated individuals with NP-C suspicion and also 7 patients with previous NP-C diagnosis under treatment with miglustat, in order to verify the cholestane-3β,5α,6β-triol value as a tool for therapy monitoring. Considering molecular assay as golden standard, it was verified that cholestane-3β,5α,6β-triol analysis presented 88% of sensitivity, 96.08% of specificity, a positive and negative predictive value calculated in 91.67% and 94.23%, respectively, for the diagnosis of NP-C. Chitotriosidase levels were increased in patients with positive molecular analysis for NP-C. For Filipin staining, it was found 1 false positive, 7 false negative and 24 inconclusive cases, showing that this assay has important limitations for NP-C diagnosis. Besides, we found a significant decrease in cholestane-3β,5α,6β-triol concentrations in NP-C patients under therapy with miglustat when compared to non-treated patients. Taken together, the present data show that cholestane-3β,5α,6β-triol analysis has a high potential to be an

Revertant Mosaicism in Heritable Skin Diseases - Mechanisms of Natural Gene Therapy

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Pasmooij, Anna M. G.; Jonkman, Marcel F.; Uitto, Jouni

Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and

Genetic Characterization of Movement Disorders and Dementias

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2018-04-27

Ataxia; Dystonia; Parkinson's Disease; Amyotrophic Lateral Sclerosis; Corticobasal Degeneration; Multiple System Atrophy; Alzheimer's Disease; Lewy Body Dementia; Parkinson Disease-Dementia; Dentatorubral-pallidoluysian Atrophy; Creutzfeldt-Jakob Disease and Fatal Familial Insomnia; Fragile X-associated Tremor/Ataxia Syndrome; Krabbe's Disease; Niemann-Pick Disease, Type C; Neuronal Ceroid Lipofuscinosis

Synthesis, Characterization, In Vitro Evaluation, and Preclinical Profiling of beta-Cyclodextrin Polyrotaxane Families for Use As Potential Niemann-Pick Type C Therapeutics

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Collins, Christopher J.

Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment. beta-Cyclodextrin (beta-CD) are natural small molecules macrocycles composed of glucose units with a hydrophobic inner cavity and hydrophilic outer rims. beta-CD derivatives have recently been shown to be effective therapeutics for NPC in cellular and animal models. In the mouse model of the disease, beta-CD therapy increases overall lifetime by as much as 50% and slows the progression of neurodegeneration. The progress has led to the initiation of a National Institutes of Health phase I clinical trial. A main drawback of beta-CD administration is the poor pharmacokinetic profile characterized by rapid renal clearance of the drug through the urine. Libraries of beta-CD derivative carrying high molecular weight polyrotaxane (PR) systems have been designed to prevent glomerular filtration of the injected beta-CD dose. An initial family of unmodified beta-CD PRs was synthesized, characterized, and their therapeutic efficacy was tested in NPC fibroblasts. This was followed by screening of PRs consisting of mixed beta-CD derivative threading featuring charged sulfobutylether beta-CD. Finally, we sought to define PR structure-property effects on in vivo pharmacokinetics, biodistribution, toxicity, immunogenicity, and protein hard corona composition. This was accomplished using a family of gadolinium carrying PRs composed of triblock Pluronic co-polymers of varying

Imaging of macrophage-related lung diseases

International Nuclear Information System (INIS)

Marten, Katharina; Hansell, David M.

2005-01-01

Macrophage-related pulmonary diseases are a heterogeneous group of disorders characterized by macrophage accumulation, activation or dysfunction. These conditions include smoking-related interstitial lung diseases, metabolic disorders such as Niemann-Pick or Gaucher disease, and rare primary lung tumors. High-resolution computed tomography abnormalities include pulmonary ground-glass opacification secondary to infiltration by macrophages, centrilobular nodules or interlobular septal thickening reflecting peribronchiolar or septal macrophage accumulation, respectively, emphysema caused by macrophage dysfunction, and honeycombing following macrophage-related lung matrix remodeling. (orig.)

Stem Cell Transplant for Inborn Errors of Metabolism

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2017-12-03

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

Use of complementary and alternative medicine by patients with lysosomal storage diseases.

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Balwani, Manisha; Fuerstman, Laura; Desnick, Robert J; Buckley, Brian; McGovern, Margaret M

2009-10-01

To evaluate the extent of complementary and alternative medicine use and perceived effectiveness in patients with lysosomal storage diseases. A 26-item survey was distributed to 495 patients with type 1 Gaucher, Fabry, and type B Niemann-Pick diseases who were seen at the Lysosomal Storage Disease Program at the Mount Sinai School of Medicine. Survey responses were entered into an access database and analyzed using descriptive statistics. Surveys were completed by 167 respondents with an overall response rate of 34%. Complementary and alternative medicines were used by 45% of patients with type 1 Gaucher disease, 41% of patients with Fabry disease, and 47% of patients with type B Niemann-Pick for symptoms related to their disease. Complementary and alternative medicines were used most frequently by adult females (55%), in patients who reported having one or more invasive procedures due to their disease, patients who use one or more conventional medical therapies, or those with depression and/or anxiety. Overall perceived effectiveness of complementary and alternative medicine supplements was low; however, complementary and alternative medicine therapies were perceived as effective. Complementary and alternative medicines are commonly used among patients with lysosomal storage diseases. Assessment of the effectiveness of these approaches in the lysosomal storage diseases is needed, and physicians should be aware of complementary and alternative medicine therapies used by patients to evaluate safety and possible drug interactions.

Four Novel p.N385K, p.V36A, c.1033–1034insT and c.1417–1418delCT Mutations in the Sphingomyelin Phosphodiesterase 1 (SMPD1 Gene in Patients with Types A and B Niemann-Pick Disease (NPD

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Masoumeh Dehghan Manshadi

2015-03-01

Full Text Available Background: Types A and B Niemann-Pick disease (NPD are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene. Methods: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. Results: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous showed the p.V36A mutation. One patient was homozygous for the c.1033–1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417–1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM protein stability, which might be evidence to suggest the pathogenicity of these mutations. Conclusion: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

A comparative study of Alzheimer's disease and Pick's disease by CT

International Nuclear Information System (INIS)

Ichimiya, Yosuke; Kobayashi, Kazunari; Arai, Heii; Ikeda, Kenji; Kosaka, Kenji

1984-01-01

17 patients with clinically diagnosed Alzheimer's disease, 11 patients with clinically diagnosed Pick's disease and 13 healthy age-matched subjects as the control were studied by computed tomography (CT). In order to study cerebral atrophy, volumetric measurement was performed. Subarachnoid Space Volume Index (SVI). Frontal, Temporal, and Parieto-Occipital Subarachnoid Space Volume Indices (SfVI, StVI, and SpoVI, respectively) as well as Ventricle Volume Index (VVI), The volume indices of anterior horn, inferior horn, and posterior horn of the lateral ventricles (VaVI, ViVI, and VpVI, respectively) were calculated as the indices for the atrophy of the cerebral cortex and white matter. Furthermore, to evaluate lobar atrophy, SfVI+VaVI (FA), StVI+ViVI (TA), and SpoVI+VpVI (POA) were defined as the indices of frontal lobe atrophy, temporal lobe atrophy, and parieto-occipital lobe atrophy respectively. In Alzheimer's patients, FA and POA were significantly large (p<0.001) in stage I group and TA was significantly enlarged (p<0.001) in stage II group. In Pick's patients, FA and TA were significantly large (FA : p<0.001, TA : p<0.01) in stage I group and POA became significantly prominent (p<0.001) in stage III group. Pick's patients showed significantly larger SfVI (p<0.2 in stage I group and p<0.001 in stage II group) and FA (p<0.01 in stage II group) than Alzheimer's patients. The results in this study give us the following suggestions; 1) Alzheimer's patients show a diffuse cerebral atrophy in the early stage. 2) Pick's patients have a localized atrophy of frontal and temporal lobes already in the early stage. 3) Compared with Alzheimer's patients, Pick's patients show significantly more severe atrophy in frontal lobe at the early stage. (J.P.N.)

Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation.

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Shamburek, R D; Pentchev, P G; Zech, L A; Blanchette-Mackie, J; Carstea, E D; VandenBroek, J M; Cooper, P S; Neufeld, E B; Phair, R D; Brewer, H B; Brady, R O; Schwartz, C C

1997-12-01

Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered [14C]mevalonate as a tracer of newly synthesized cholesterol and [3H]cholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free [14C]- and free [3H]cholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of [3H]cholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free [14C] cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free [3H]cholesterol derived from HDL, observed before extensive exchange occurred of the [3H]cholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free [3H]cholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro

Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases

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N. V. Olkhovych

2016-02-01

Full Text Available To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244 that is higher than in European population. It was indicated that molecular-genetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Science.gov (United States)

Hollak, C E M; de Sonnaville, E S V; Cassiman, D; Linthorst, G E; Groener, J E; Morava, E; Wevers, R A; Mannens, M; Aerts, J M F G; Meersseman, W; Akkerman, E; Niezen-Koning, K E; Mulder, M F; Visser, G; Wijburg, F A; Lefeber, D; Poorthuis, B J H M

2012-11-01

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone

Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

Science.gov (United States)

2017-11-15

Hurler Syndrome (MPS I); Hurler-Scheie Syndrome; Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.

Science.gov (United States)

Muro, Silvia; Schuchman, Edward H; Muzykantov, Vladimir R

2006-01-01

Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders.

Science.gov (United States)

Rappaport, Jeff; Manthe, Rachel L; Solomon, Melani; Garnacho, Carmen; Muro, Silvia

2016-02-01

Many cellular activities and pharmaceutical interventions involve endocytosis and delivery to lysosomes for processing. Hence, lysosomal processing defects can cause cell and tissue damage, as in lysosomal storage diseases (LSDs) characterized by lysosomal accumulation of undegraded materials. This storage causes endocytic and trafficking alterations, which exacerbate disease and hinder treatment. However, there have been no systematic studies comparing different endocytic routes in LSDs. Here, we used genetic and pharmacological models of four LSDs (type A Niemann-Pick, type C Niemann-Pick, Fabry, and Gaucher diseases) and evaluated the pinocytic and receptor-mediated activity of the clathrin-, caveolae-, and macropinocytic routes. Bulk pinocytosis was diminished in all diseases, suggesting a generic endocytic alteration linked to lysosomal storage. Fluid-phase (dextran) and ligand (transferrin) uptake via the clathrin route were lower for all LSDs. Fluid-phase and ligand (cholera toxin B) uptake via the caveolar route were both affected but less acutely in Fabry or Gaucher diseases. Epidermal growth factor-induced macropinocytosis was altered in Niemann-Pick cells but not other LSDs. Intracellular trafficking of ligands was also distorted in LSD versus wild-type cells. The extent of these endocytic alterations paralleled the level of cholesterol storage in disease cell lines. Confirming this, pharmacological induction of cholesterol storage in wild-type cells disrupted endocytosis, and model therapeutics restored uptake in proportion to their efficacy in attenuating storage. This suggests a proportional and reversible relationship between endocytosis and lipid (cholesterol) storage. By analogy, the accumulation of biological material in other diseases, or foreign material from drugs or their carriers, may cause similar deficits, warranting further investigation.

Psychosocial dysfunction associated with skin picking disorder and trichotillomania

DEFF Research Database (Denmark)

Grant, Jon E.; Redden, Sarah A.; Leppink, Eric W.

2016-01-01

Skin picking disorder (SPD) and trichotillomania (TTM) are common and oftentimes disabling disorders. 125 Participants with SPD and 152 with TTM undertook clinical and neurocognitive evaluation, and were grouped according to mild, moderate, or severe levels of psychosocial dysfunction. Relationsh......Skin picking disorder (SPD) and trichotillomania (TTM) are common and oftentimes disabling disorders. 125 Participants with SPD and 152 with TTM undertook clinical and neurocognitive evaluation, and were grouped according to mild, moderate, or severe levels of psychosocial dysfunction...... that levels of self-reported psychosocial dysfunction have a strong association with specific clinical aspects of SPD and TTM....

Protein complexes and cholesterol in the control of late endosomal dynamicsCholesterol and multi-protein complexes in the control of late endosomal dynamics

NARCIS (Netherlands)

Kant, Rik Henricus Nicolaas van der

2013-01-01

Late endosomal transport is disrupted in several diseases such as Niemann-Pick type C, ARC syndrome and Alzheimer’s disease. This thesis describes the regulation of late endosomal dynamics by cholesterol and multi-protein complexes. We find that cholesterol acts as a cellular tomtom that steers the

Longitudinal Study of Neurodegenerative Disorders

Science.gov (United States)

2018-01-31

MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

Lysosomal lipid storage diseases.

Science.gov (United States)

Schulze, Heike; Sandhoff, Konrad

2011-06-01

Lysosomal lipid storage diseases, or lipidoses, are inherited metabolic disorders in which typically lipids accumulate in cells and tissues. Complex lipids, such as glycosphingolipids, are constitutively degraded within the endolysosomal system by soluble hydrolytic enzymes with the help of lipid binding proteins in a sequential manner. Because of a functionally impaired hydrolase or auxiliary protein, their lipid substrates cannot be degraded, accumulate in the lysosome, and slowly spread to other intracellular membranes. In Niemann-Pick type C disease, cholesterol transport is impaired and unesterified cholesterol accumulates in the late endosome. In most lysosomal lipid storage diseases, the accumulation of one or few lipids leads to the coprecipitation of other hydrophobic substances in the endolysosomal system, such as lipids and proteins, causing a "traffic jam." This can impair lysosomal function, such as delivery of nutrients through the endolysosomal system, leading to a state of cellular starvation. Therapeutic approaches are currently restricted to mild forms of diseases with significant residual catabolic activities and without brain involvement.

Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: By tandem mass spectrometry

Directory of Open Access Journals (Sweden)

Susan Elliott

2016-09-01

Full Text Available In this data article we provide a detailed standard operating procedure for performing a tandem mass spectrometry, multiplex assay of 6 lysosomal enzymes for newborn screening of the lysosomal storage diseases Mucopolysaccharidosis-I, Pompe, Fabry, Niemann-Pick-A/B, Gaucher, and Krabbe, (Elliott, et al., 2016 [1]. We also provide the mass spectrometry peak areas for the product and internal standard ions typically observed with a dried blood spot punch from a random newborn, and we provide the daily variation of the daily mean activities for all 6 enzymes.

Skin Picking Disorder

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Pinar Cetinay Aydin

2014-08-01

Full Text Available Skin picking disorder is not a dermatological disorder and it is a table characterized with picking skin excessively and repetitively, leading to damage in skin tissue. Unlike normal picking behaviour, psychogenic skin picking is repetitive and it can lead to severe damage in the skin and even complications which constitute vital danger. While some patients define frequent but short lasting picking attacks, others define rarer attacks which last a few hours. Skin picking disorder, which is not included in the classification systems up to DSM-5 as a separate diagnosis category, is included as an independent diagnosis in Obsessive Compulsive Disorder and Associated Disorders category in DSM-5. In case reports, open label studies and double blind studies selective serotonin reuptake inhibitors are shown to be effective in the treatment of skin picking disorder. Mostly, cognitive-behaviourial techniques are used and have been proven to be useful in psychotherapy. Habit reversal is one of the behaviourial techniques which are frequently applied, give positive results in which well-being state can be maintained. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(4.000: 401-428

Extinction Partially Reverts Structural Changes Associated with Remote Fear Memory

Science.gov (United States)

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni; Aceti, Massimiliano; Lumaca, Massimo; Ammassari-Teule, Martine

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear…

Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.

Science.gov (United States)

Voorink-Moret, M; Goorden, S M I; van Kuilenburg, A B P; Wijburg, F A; Ghauharali-van der Vlugt, J M M; Beers-Stet, F S; Zoetekouw, A; Kulik, W; Hollak, C E M; Vaz, F M

2018-02-01

In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders. A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic review of the literature was performed to assess the usefulness of these biochemical markers. Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3β,5α,6β-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly

Exploring the role of picker personality in predicting picking performance with pick by voice, pick to light and RF-terminal picking

NARCIS (Netherlands)

de Vries, J.; de Koster, R.; Stam, D.

2016-01-01

Order pickers and individual differences between them could have a substantial impact on picking performance, but are largely ignored in studies on order picking. This paper explores the role of individual differences in picking performance with various picking tools (pick by voice, RF-terminal

Extinction partially reverts structural changes associated with remote fear memory

DEFF Research Database (Denmark)

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic...... the remote memory network, suggesting that the preserved network properties might sustain reactivation of extinguished conditioned fear....

Feather-picking psittacines: histopathology and species trends.

Science.gov (United States)

Garner, M M; Clubb, S L; Mitchell, M A; Brown, L

2008-05-01

Histologic findings are described for 408 feather-picking or self-mutilating psittacines with the use of biopsies from clinically affected and unaffected skin. Inflammatory skin disease was diagnosed in 210 birds, and traumatic skin disease was diagnosed in 198 birds. Criteria used for the diagnosis of inflammatory skin disease included the presence of perivascular inflammation in the superficial or deep dermis of clinically affected and unaffected sites. The primary histologic criteria for the diagnosis of traumatic skin disease were superficial dermal scarring with or without inflammation in the affected sites and an absence of inflammation in the unaffected sites. The inflammatory cells associated with the lesions were typically lymphocytes and occasionally plasma cells, histiocytes, and granulocytes. A preponderance of inflammatory skin disease was seen in macaws (Ara spp.) and Amazon parrots (Amazona spp.). A preponderance of traumatic skin disease was seen in cockatoos (Cacatua spp.) and African grey parrots (Psittacus erithacus). The prevalence of each was approximately equal in several other species, including conures (Aratinga and Pyrrhura spp.), eclectus parrots (Eclectus roratus), quaker parrots (Myiopsitta monachus), cockatiels (Nymphicus hollandicus), parakeets (Cyanorhamphus and Psittacula spp.), and caiques (Pionites spp.). No geographic or gender-based trends were identified. These findings could be helpful for identifying and treating birds with feather-picking disorders.

Skin picking disorder in university students

DEFF Research Database (Denmark)

Odlaug, Brian Lawrence; Lust, Katherine; Schreiber, Liana R N

2013-01-01

This study sought to examine the prevalence of skin picking disorder (SPD) in a university sample and assess associated physical and mental health correlates.......This study sought to examine the prevalence of skin picking disorder (SPD) in a university sample and assess associated physical and mental health correlates....

Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

Science.gov (United States)

Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma Del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo

2017-05-01

To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS. Copyright © 2017 Elsevier Inc. All rights reserved.

Reverted austenite in PH 13-8 Mo maraging steels

International Nuclear Information System (INIS)

Schnitzer, Ronald; Radis, Rene; Noehrer, Matthias; Schober, Michael; Hochfellner, Rainer; Zinner, Silvia; Povoden-Karadeniz, E.; Kozeschnik, Ernst; Leitner, Harald

2010-01-01

The mechanical properties of maraging steels are strongly influenced by the presence of reverted austenite. In this study, the morphology and chemical composition of reverted austenite in a corrosion resistant maraging steel was characterized using transmission electron microscopy (TEM) and atom probe tomography (APT). Two types of austenite, i.e. granular and elongated, are present after aging at 575 o C, whereby the content of the latter increases during aging. The investigations revealed that the austenite phase is enriched in Ni, which prevents the transformation to martensite during cooling. Inside and next to the austenitc areas, Mo and Cr-rich carbides, which form during the aging treatment, were found. Various aging treatments were performed to obtain the activation energy for the formation of reverted austenite. Additionally, the experimental data are compared with thermodynamic and kinetic simulations. Based on these results and the chemical composition changes of the phases, a model for the formation of reverted austenite is presented. It is concluded that precipitation of B2-ordered NiAl and formation of reverted austenite take place simultaneously during aging and that dissolution of precipitates is not essential for the initial formation of reverted austenite.

Extinction partially reverts structural changes associated with remote fear memory

DEFF Research Database (Denmark)

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic...... (ILC) cortices 36 d following contextual fear conditioning. Upon extinction, aCC spine density returned to baseline, but the enhanced proportion of large spines did not. Differently, ILC spine density remained elevated, but the size of spines decreased dramatically. Thus, extinction partially erases...

A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies.

Directory of Open Access Journals (Sweden)

Edward Rockenstein

Full Text Available Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer's disease, three-repeat (3R Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations. Two lines expressing high (Line 13 and low (Line 2 levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick's-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the

Haloperidol augmentation of fluvoxamine in skin picking disorder: a case report

Directory of Open Access Journals (Sweden)

Luca Maria

2012-07-01

Full Text Available Abstract Introduction Compulsive skin picking, being part of the broader category of impulse control disorders, is considered a residual diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. It is characterized by excessive scratching or picking of normal skin, or skin with minor surface irregularities, and occurs in 2% of patients attending dermatology clinics. Despite the clinical relevance of this disorder, no clear guidelines are available yet; clinical management is, therefore, compromised and the day-to-day clinical practice is burdened by difficulties. Studies on selective serotonin reuptake inhibitors and anti-epileptic drugs have provided limited results. The association between anti-depressants and anti-epileptics has been found to be beneficial in some impulse control disorders, but in skin picking no previous studies have been conducted on this pharmacological approach. There are very few reports on the efficacy of anti-psychotics in skin picking. Case presentation The therapeutic path described in this case report produced good results for a 59-year-old Caucasian woman. The first therapeutic approach, with fluvoxamine and oxcarbazepine was partially effective; then, the suspension of oxcarbazepine and haloperidol augmentation of fluvoxamine were adopted. After 10 weeks, a significant improvement of the disease was observed: the clinical picture and the associated symptoms were nearly solved. Conclusions To the best of our knowledge, this is the first article reporting the association of fluvoxamine and haloperidol in skin picking disorder. It might be useful to perform further research regarding the treatment of skin picking disorder: in clinical practice, several variables might limit the choice of certain drugs. Therefore, it would be useful for the clinician to be aware of other therapeutic options.

Making the Right Pick: Aligning Order Picking Methods, Incentive Systems and Regulatory Focus to Increase Picking Performance

NARCIS (Netherlands)

J. de Vries (Jelle); M.B.M. de Koster (René); D.A. Stam (Daan)

2015-01-01

textabstractA unique controlled field experiment investigates order picking performance (in terms of productivity, quality, and job satisfaction). We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems

Mean-Reverting Portfolio With Budget Constraint

Science.gov (United States)

Zhao, Ziping; Palomar, Daniel P.

2018-05-01

This paper considers the mean-reverting portfolio design problem arising from statistical arbitrage in the financial markets. We first propose a general problem formulation aimed at finding a portfolio of underlying component assets by optimizing a mean-reversion criterion characterizing the mean-reversion strength, taking into consideration the variance of the portfolio and an investment budget constraint. Then several specific problems are considered based on the general formulation, and efficient algorithms are proposed. Numerical results on both synthetic and market data show that our proposed mean-reverting portfolio design methods can generate consistent profits and outperform the traditional design methods and the benchmark methods in the literature.

Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly

Science.gov (United States)

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart diseas...

Modulation of the maladaptive stress response to manage diseases of protein folding.

Directory of Open Access Journals (Sweden)

Daniela Martino Roth

2014-11-01

Full Text Available Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD, Niemann-Pick type C1 disease (NPC1, Alzheimer's disease (AD, and cystic fibrosis (CF. Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR, through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.

Lysosomal storage diseases

Science.gov (United States)

Ferreira, Carlos R.; Gahl, William A.

2016-01-01

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively. PMID:29152458

Plant height revertants of Dominant Semidwarf mutant rice created by low-energy ion irradiation

Energy Technology Data Exchange (ETDEWEB)

Liu Binmei [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Wu Yuejin [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China)], E-mail: yjwu@ipp.ac.cn; Xu Xue; Song, M.; Zhao, M. [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Fu, X.D. [Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101 (China)

2008-04-15

Dominant Semidwarf mutant rice (Sdd) was obtained from its wild type (WT) by irradiation with a low-energy ion beam. Six tall revertants of Sdd were induced by irradiation. The revertants restored the plant height to that of WT plants. Investigation of the agronomic character and genetic analysis indicate that the revertants are similar to WT plants with putative different inherited mutations. The revertants were checked for DNA differences using the simple sequence repeat technique. Among 408 such primers used, only 2 primers detected mutation sites in the revertants, which provided the molecular evidence for the revertants induced from Sdd. This study indicates that ion irradiation may be used as a mutagen to create revertants for plant architecture studies and could be a new application.

Semi-Automated Digital Image Analysis of Pick's Disease and TDP-43 Proteinopathy.

Science.gov (United States)

Irwin, David J; Byrne, Matthew D; McMillan, Corey T; Cooper, Felicia; Arnold, Steven E; Lee, Edward B; Van Deerlin, Vivianna M; Xie, Sharon X; Lee, Virginia M-Y; Grossman, Murray; Trojanowski, John Q

2016-01-01

Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes. © The Author(s) 2015.

Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

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Kei Nakajima

2012-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH are multidisciplinary liver diseases that often accompany type 2 diabetes or metabolic syndrome, which are characterized by insulin resistance. Therefore, effective treatment of type 2 diabetes and metabolic syndrome should target not only the cardiometabolic abnormalities, but also the associated liver disorders. In the last decade, it has been shown that metformin, thiazolidinediones, vitamin E, ezetimibe, n-3 polyunsaturated fatty acids, renin-angiotensin system (RAS blockers, and antiobesity drugs may improve hepatic pathophysiological disorders as well as clinical parameters. Accordingly, insulin sensitizers, antioxidative agents, Niemann-Pick C1-like 1 (NPC1L1 inhibitors, RAS blockers, and drugs that target the central nervous system may represent candidate pharmacotherapies for NAFLD and possibly NASH. However, the efficacy, safety, and tolerability of long-term treatment (potentially for many years with these drugs have not been fully established. Furthermore, clinical trials have not comprehensively examined the efficacy of lipid-lowering drugs (i.e., statins, fibrates, and NPC1L1 inhibitors for the treatment of NAFLD. Although clinical evidence for RAS blockers and incretin-based agents (GLP-1 analogs and dipeptidyl peptidase-4 inhibitors is also lacking, these agents are promising in terms of their insulin-sensitizing and anti-inflammatory effects without causing weight gain.

Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis

OpenAIRE

Elrick, Matthew J.; Lieberman, Andrew P.

2013-01-01

Alterations in macroautophagy (hereafter referred to as “autophagy”) are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lip...

Large-scale computational drug repositioning to find treatments for rare diseases.

Science.gov (United States)

Govindaraj, Rajiv Gandhi; Naderi, Misagh; Singha, Manali; Lemoine, Jeffrey; Brylinski, Michal

2018-01-01

Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed e MatchSite, a new computer program to compare drug-binding sites. In this study, e MatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

Gaucher disease and other storage disorders.

Science.gov (United States)

Grabowski, Gregory A

2012-01-01

In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

Reverters from PD-MCI to cognitively intact are at risk for future cognitive impairment: Analysis of the PPMI cohort.

Science.gov (United States)

Jones, Jacob D; Kuhn, Taylor P; Szymkowicz, Sarah M

2018-02-01

Past studies have shown that a large portion of individuals with Parkinson's disease (PD) and mild cognitive impairment (MCI) will revert to a cognitively intact (CI) status in the future. Aging studies have shown that individuals who revert from MCI to CI are at increased risk for reconverting to MCI or dementia in the future. The current study examined if individuals who revert from PD-mild cognitive impairment (PD-MCI) to CI will be at increased risk for future PD-MCI and Parkinson's disease dementia (PDD). The study utilized data from the Parkinson's Progression Markers Initiative (PPMI). The sample included 364 newly diagnosed PD participants who were followed annually for up to 4 years. Based on the first and second assessments, we identified individuals who were CI at each assessment (CI-Stable) and individuals who were PD-MCI at baseline but then reverted to CI (Reversion). Analyses examined if participants in the Reversion group were at greater risk, relative to the CI-Stable group, for cognitive impairment at future assessments. Participants in the Reversion group were at greater risk for future cognitive impairment (PD-MCI or PDD) at the 2nd, 3rd and 4th annual follow-up, relative to the CI-Stable group. The Reversion group continued to be at increased risk for future cognitive impairment when adjusting for age, gender, education, depressive symptoms, and motor severity. A large proportion of individuals with PD-MCI will not show evidence of cognitive impairment within a year. However, these "reverters" continue to be at risk for future development of cognitive impairment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease.

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Yazi D Ke

Full Text Available Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD and frontotemporal lobar degeneration (FTLD. Here, we performed an unbiased SAGE (serial analysis of gene expression of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD, and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

Pick 'n' mix: neuropatholgical detection of peri-tumour taupathy.

LENUS (Irish Health Repository)

Lonergan, Roisin

2013-11-01

Radiotherapy is used to treat recurrent oligodendrogliomas, WHO grade 2 tumours. Potential morbitities include steroid-responsive radiation necrosis and radiation leucoencephalopathy, characterised pathologically by reactive astrogliosis, focal necrosis, demyelination, axonal loss, and clinically by progressive subcortical deficits (ataxia, amnesia, incontinence, cognitive decline), with relative sparing of cortical function. Although subcortical features may overlap with neurodegenerative conditions (eg frontotemporal dementia), focal cortical atrophy of FTD causes loss of language function in addition to memory, and specific histopathological features characterise FTD subtypes (eg Pick disease). Association between mitotic disease and tauopathy has not been reported widely, but co-existence is possible. Diagnostic accuracy may guide management.

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism[S

Science.gov (United States)

Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi-Vici, Carlo

2016-01-01

Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient’s age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. PMID:26733147

Application of closed queueing network in the performance of a pick-and-pass order picking system

NARCIS (Netherlands)

Gaast, van der J.P.; Koster, de M.B.M.; Adan, I.J.B.F.; Resing, J.A.C.

2011-01-01

This paper presents a method for obtaining approximate solutions for pick-and-pass order picking systems with multiple classes of orders. The pick-and-pass system is decomposed into an entrance station, conveyor nodes and pick stations. A customer order needs to visit multiple pick stations, but the

PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.

Science.gov (United States)

Lu, Wei; Ziff, Edward B

2005-08-04

PICK1 and ABP/GRIP bind to the AMPA receptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.

Alterations in membrane trafficking and pathophysiological implications in lysosomal storage disorders.

Science.gov (United States)

Kuech, Eva-Maria; Brogden, Graham; Naim, Hassan Y

2016-11-01

Lysosomal storage disorders are a heterogeneous group of more than 50 distinct inborn metabolic diseases affecting about 1 in 5000 to 7000 live births. The diseases often result from mutations followed by functional deficiencies of enzymes or transporters within the acidic environment of the lysosome, which mediate the degradation of a wide subset of substrates, including glycosphingolipids, glycosaminoglycans, cholesterol, glycogen, oligosaccharides, peptides and glycoproteins, or the export of the respective degradation products from the lysosomes. The progressive accumulation of uncleaved substrates occurs in multiple organs and finally causes a broad spectrum of different pathologies including visceral, neurological, skeletal and hematologic manifestations. Besides deficient lysosomal enzymes and transporters other defects may lead to lysosomal storage disorders, including activator defects, membrane defects or defects in modifier proteins. In this review we concentrate on four different lysosomal storage disorders: Niemann-Pick type C, Fabry disease, Gaucher disease and Pompe disease. While the last three are caused by defective lysosomal hydrolases, Niemann-Pick type C is caused by the inability to export LDL-derived cholesterol out of the lysosome. We want to emphasise potential implications of membrane trafficking defects on the pathology of these diseases, as many mutations interfere with correct lysosomal protein trafficking and alter cellular lipid homeostasis. Current therapeutic strategies are summarised, including substrate reduction therapy as well as pharmacological chaperone therapy which directly aim to improve folding and lysosomal transport of misfolded mutant proteins. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Picking Robot Arm Trajectory Planning Method

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Zhang Zhiyong

2014-01-01

Full Text Available The picking robot arm is scheduled to complete picking tasks in the working space, to overcome the shaking vibration to improve the picking stability, its movement should follow specific consistence trajectory points. Usually we should give definite multiple feature picking points, map their inverse kinematics to the joint space, establish motion equation for the corresponding point in the joint space, then follow these equations motion for the interpolation on the joint so that we can meet the movement requirements. Trajectory planning is decisive significance for accuracy and stability of controlling robot arm. The key issue that picking arm complete picking task will be come true by trajectory planning, namely, robot arm track the desired trajectory. which based on kinematics and statics picking analysis in a joint space according to the requirements of picking tasks, and obtain the position and orientation for picking robot arm, study and calculate the theory of trajectory parameters timely.

Put order picking system

Directory of Open Access Journals (Sweden)

Đurđević Dragan D.

2014-01-01

Full Text Available Nowadays the warehouse is very important logistic component of the supply chain, where order-picking systems have important role. Due to the significant impact on logistics performance permanent goals are to increase efficiency and reduce the cost of these systems. To achieve these goals, there are different researches, and their success is determined by the achieved performances. Performances order picking process are dependent on the applied technology concepts of order-picking system, as well as the ways in which it is organized and managed. In addition to the standard conceptions (the man to good and good to the man is one of the newer, so-called. 'put' system - the inverse order-picking. The aim of this paper is to describe this concept, point out its core strengths and weaknesses and provide a basis that may be of importance in the development of warehouse technological solutions and application of this order-picking systems concept.

Evaluation by statistical brain perfusion SPECT analysis on MRI findings, kana pick-out test and Mini-Mental State Examination results in patients with forgetfulness

International Nuclear Information System (INIS)

Nakatsuka, Hiroki; Matsubara, Ichirou; Ohtani, Haruhiko

2003-01-01

The aim of this single photon emission computed tomography (SPECT) study was to determine the abnormality of the regional cerebral blood flow (rCBF) using a three-dimensional stereotactic surface projection (3D-SSP) in 18 patients who were referred to the hospital because of forgetfulness. Two intergroup comparison by 3D-SSP analysis was conducted based on MRI, kana pick-out test and Mini-Mental State Examination (MMSE) results. Of the MRI findings, in the brain atrophy group, rCBF was decreased in the posterior cingulate gyrus, medial temporal structure and parieto-temporal association cortex; these rCBF-decreased areas are similar to the Alzheimer disease pattern. In the group where the MMSE was normal but the kana pick-out test was abnormal, rCBF was decreased in the posterior cingulate gyrus and cinguloparietal transitional area. In the group where both the MMSE and kana pick-out test were abnormal, rCBF was decreased in the parieto-temporal association cortex, temporal cortex and medial temporal structure. These results suggest that 3D-SSP analysis of the SPECT with MMSE and the kana pick-out test provides the possibility of early diagnosis of initial stage of Alzheimer's disease. (author)

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism.

Science.gov (United States)

Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi-Vici, Carlo

2016-03-01

Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient's age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Postoperative respiratory outcomes in laparoscopic bariatric surgery: comparison of a prospective group of patients whose neuromuscular blockade was reverted with sugammadex and a historical one reverted with neostigmine.

Science.gov (United States)

Llauradó, S; Sabaté, A; Ferreres, E; Camprubí, I; Cabrera, A

2014-12-01

Bariatric surgery patients are at high risk of perioperative respiratory adverse events. We hypothesized that the use of sugammadex to reverse neuromuscular blockade could improve postoperative respiratory outcomes. Prospective observational series of consecutive patients scheduled for laparoscopic bariatric surgery in whom neuromuscular blockade was reverted with sugammadex were compared with a historical matched cohort of patients reverted with neostigmines. The necessity of postoperative mechanical ventilation or pathological changes in postoperative chest X-ray were two of the comparisons done. We enrolled 160 patients in each group (Sugammadex - SG and Historical - HG). Two patients (mean, CI 95%), (1.25, 0.34-4.4) in the SG and five patients in the HG (mean, CI 95%), (3.13, 1.34-7.11) required mechanical ventilation immediately after surgery (p=0.38, chi-square test). Significantly less chest X-ray postoperative changes were observed in the SG: 11 patients (6.9%) versus 26 patients (16.3%) in the HG (Odds ratio OR, CI 95%) (0.36, 0.18-0.8). Requirement of mechanical ventilation is not associated to the reversal agent employed. Less pathological postoperative chest X-ray changes were found in the group of patients whose neuromuscular blockade was reverted with sugammadex. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

Science.gov (United States)

Miller, Patricia A; Mulla, Sohail M; Adams-Webber, Thomasin; Sivji, Yasmin; Guyatt, Gordon H; Johnston, Bradley C

2016-01-01

To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

Are Current Accounts of Asian Economies Mean-reverting?: Nonlinear Unit Root Test Approach

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Bonghan Kim

2005-12-01

Full Text Available This paper tests the mean reverting property of current account in the financial crisis-affected 5 counties of southeast Asia using nonlinear unit root tests of Park and shintani(2004. Our approach is based on the idea that a conventional unit root test has lower power in detecting the nonlinear mean reverting behavior if the current account follows a nonlinear mean reversion process. We obtained following empirical results. First, for the pre-crisis period (1981Q1-1996Q4, the current accounts of Indonesia, Malaysia and Philippines are mean-reverting but those of Korea and Thailand are not mean-reverting. Second, for the full sample period (1981Q1-2003Q4, the ADF test fails to reject the unit root of the current account in all countries except Philippines. However, unit root is rejected in favor of nonlinear mean reversion except Thailand. This nonlinear unit root test result implies that crisis-affected Asian countries except Thailand have sustainable paths of current accounts. Third, when the current accounts of East Asian countries are nonlinear mean-reverting, the mean reverting process can be well described by the ESTAR model, instead of the DTAR or DLSTAR model. The nonlinear unit root test results imply smooth nonlinear mean-reversion behaviors of East Asian current accounts. Finally, the shape of estimated impulse response functions becomes steeper as the size of shock increases, which is the very characteristic of the nonlinear process.

A REVIEW OF ORDER PICKING IMPROVEMENT METHODS

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Johan Oscar Ong

2014-09-01

Full Text Available As a crucial and one of the most important parts of warehousing, order picking often raises discussion between warehousing professionals, resulting in various studies aiming to analyze how order picking activity can be improved from various perspective. This paper reviews various past researches on order picking improvement, and the various methods those studies analyzed or developed. This literature review is based on twenty research articles on order picking improvement viewed from four different perspectives: Automation (specifically, stock-to-picker system, storage assignment policy, order batching, and order picking sequencing. By reviewing these studies, we try to identify the most prevalent order picking improvement approach to order picking improvement. Keywords: warehousing; stock-to-picker; storage assignment; order batching; order picking sequencing; improvement

Prenatal-Onset Niemann–Pick Type C Disease with Nonimmune Hydrops Fetalis

Directory of Open Access Journals (Sweden)

Ozge Surmeli-Onay

2013-10-01

Full Text Available Niemann–Pick type C (NPC; OMIM 257219 disease is a neurodegenerative lysosomal storage disorder characterized by accumulation of unesterified cholesterol in the lysosomal/late endosomal system. This autosomal recessive disorder occurs in approximately 1/150,000 births. The broad clinical spectrum ranges from a prenatal severe presentation to an adult-onset chronic neurodegenerative disease. Data about prenatal presentation of NPC are limited. A female newborn was born at 342 weeks' gestation with a birth weight of 3070 g, and transferred to the Neonatal Intensive Care Unit because of nonimmune hydrops fetalis (NIHF and respiratory distress. On admission, a physical examination revealed skin edema, mild respiratory distress, and abdominal distention due to massive ascites. Hepatosplenomegaly and cholestasis increased progressively and bleeding diathesis occurred. Results of an abdominal ultrasonography showed hepatosplenomegaly and segmental multicystic dysplastic left kidney. Foamy cells with a lysosomal phospholipid storage pattern compatible with NPC were found in the bone marrow smear. Cultured fibroblasts showed a strongly elevated filipin staining (classical NPC cellular phenotype, establishing the diagnosis of NPC. The infant died on the 52nd day of life because of respiratory distress due to lung involvement of NPC, massive ascites, and progressive liver failure. Results of an autopsy showed multiorgan storage disease involving the liver, spleen, lymph nodes, thymus, lungs, and brain. Here, we present a preterm infant with NIHF as a sign of severe prenatal-onset NPC and review the literature.

Outline of metabolic diseases in adult neurology.

Science.gov (United States)

Mochel, F

2015-01-01

Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available. Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises - acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided - GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases - ornithine transcarbamylase deficiency and adrenoleukodystrophy - and recommended in maternally inherited mitochondrial diseases - mutations of mitochondrial DNA. Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Effect of Cr Contents and Heat Treating on Reverted Austenite in Maraging Steel Weldments

Science.gov (United States)

Kim, S. W.; Lee, H. W.

2018-05-01

By conducting flux cored arc welding (FCAW) on maraging steels with Cr contents of 1.4 and 5.2 wt%, this study observed the effects of Cr content and heat treating on reverted austenite formation in welded maraging steel. Aging treatment was carried out at the temperatures of 450, 480 and 530 °C for 3 h in each condition. As the aging temperature increased, reverted austenite was formed along the interdendritic and intercellular grain boundaries, and the proportion of reverted austenite increased with increasing Cr addition. The aging process led to the segregation of Ti and Mo along the interdendritic and intercellular grain boundaries. Some of the welded specimens were subjected to solution heat treatment at 820 and 1250 °C for 1 h after welding, resulting in a decrease in reverted austenite fraction.

Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

Science.gov (United States)

Korber, Martina; Klein, Isabella; Daum, Günther

2017-12-01

Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described. Copyright © 2017 Elsevier B.V. All rights reserved.

Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.

Science.gov (United States)

Park, Soonhong; Ahuja, Malini; Kim, Min Seuk; Brailoiu, G Cristina; Jha, Archana; Zeng, Mei; Baydyuk, Maryna; Wu, Ling-Gang; Wassif, Christopher A; Porter, Forbes D; Zerfas, Patricia M; Eckhaus, Michael A; Brailoiu, Eugen; Shin, Dong Min; Muallem, Shmuel

2016-02-01

Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV. © 2015 The Authors.

'Limits and current knowledge of Pick's disease: its differential diagnosis'. A translation of the 1957 Delay, Brion, Escourolle article.

Science.gov (United States)

Thibodeau, Marie-Pierre; Miller, Bruce L

2013-01-01

This article is a translation of a French article by Delay, Brion, and Escourolle. In a seminal article published in French in 1957 these authors summarized the work of previous researchers and reviewed a wide sample of frontotemporal dementia (FTD) cases formerly referred to as Pick's disease. The authors were among the first to define the critical clinical and anatomical differences between Alzheimer's disease (AD) and FTD and they even delineated distinctive FTD subtypes making possible the advances that now constitute the base of our studies. Reviewing their work allows us to appreciate the progress research has made.

Reverting urban exotic pine forests to Macchia and indigenous ...

African Journals Online (AJOL)

Reverting urban exotic pine forests to Macchia and indigenous forest ... Harvesting operations were planned to make the transition from high open ... Key words: Strip-cutting, Cable yarding, Participatory planning, Shelterwood, Urban forests ...

Use of ergonomic principles in manual order picking systems

Directory of Open Access Journals (Sweden)

Labus Nina

2018-02-01

Full Text Available Successful companies are continually striving to streamline costs and optimize processes, enabling them to grow progress, develop and ensure competitiveness on the market. A large part of the costs arises in warehouses, where up to 55% of total costs are generated by order-picking, which makes it important and interesting in terms of research. The paper explores “picker to part” order-picking concept, which enables flexible work and is the optimal choice for most companies. The concept is associated with a high level of work-related injuries and work-related illnesses. Work requires physical efforts resulting from handling heavy goods, performing repetitive movements and using manipulative means. Human as the main actor of the concept affects the costs caused by picking and the quality of work done, which depends on technological support, physically and psychologically capable and motivated people. Due to the high costs of service, the focus on time planning and productivity increases. Contrary, the lack of attention is paid to the working conditions and the health status of the pickers. To overcome this gab, a review of scientific and professional literature on ergonomic principles in picking concept »picker to part« was carried out, followed by a quantitative survey of ergonomic properties in warehousing activities. Results revealed that more than 60% of the surveyed order-pickers associate problems with health with the characteristics of work, about 24% of them associate health problems with the use of a particular means of transport, and all agree that provided measures to reduce physical effort and greater support of technologies influence on increased speed of work and better health status of order-pickers.

Determining stress fields of shearer-loader picks

Energy Technology Data Exchange (ETDEWEB)

Luszczkiewicz, J; Sikora, W

1987-06-01

Analyzes factors which influence stress distribution in the NK-4 shearer-loader picks during coal cutting. The AFT optically active cover, 0.0015 mm thick, was used. The pick with the AFT cover was loaded using a force of 33 kN. Isoclinic lines showing stress distribution were photographed. Effects of pick design and its holder type on stress distribution were investigated. Investigations showed that distribution of normal stresses in a pick shaft has a non-linear character. The hole in a pick shaft increased stress concentration in that shaft section. Eliminating the hole reduced stress concentration. Reducing shaft length by about 20 mm did not increase stresses in that shaft zone. 15 refs.

Automatic traveltime picking using instantaneous traveltime

KAUST Repository

Saragiotis, Christos; Alkhalifah, Tariq Ali; Fomel, Sergey

2013-01-01

Event picking is used in many steps of seismic processing. We present an automatic event picking method that is based on a new attribute of seismic signals, instantaneous traveltime. The calculation of the instantaneous traveltime consists of two separate but interrelated stages. First, a trace is mapped onto the time-frequency domain. Then the time-frequency representation is mapped back onto the time domain by an appropriate operation. The computed instantaneous traveltime equals the recording time at those instances at which there is a seismic event, a feature that is used to pick the events. We analyzed the concept of the instantaneous traveltime and demonstrated the application of our automatic picking method on dynamite and Vibroseis field data.

Automatic traveltime picking using instantaneous traveltime

KAUST Repository

Saragiotis, Christos

2013-02-08

Event picking is used in many steps of seismic processing. We present an automatic event picking method that is based on a new attribute of seismic signals, instantaneous traveltime. The calculation of the instantaneous traveltime consists of two separate but interrelated stages. First, a trace is mapped onto the time-frequency domain. Then the time-frequency representation is mapped back onto the time domain by an appropriate operation. The computed instantaneous traveltime equals the recording time at those instances at which there is a seismic event, a feature that is used to pick the events. We analyzed the concept of the instantaneous traveltime and demonstrated the application of our automatic picking method on dynamite and Vibroseis field data.

PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance

DEFF Research Database (Denmark)

Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M

2013-01-01

by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate...

Pick-up and impact of flexible bodies

Science.gov (United States)

Singh, H.; Hanna, J. A.

2017-09-01

Picking up, laying down, colliding, rolling, and peeling are partial-contact interactions involving moving discontinuities. We examine the balances of momentum and energy across a moving discontinuity in a string, with allowance for injection or dissipation by singular supplies. We split the energy dissipation according to its invariance properties, discuss analogies with systems of particles and connections with the literature on shocks and phase transition fronts in various bodies, and derive a compatibility relation between supplies of momentum and translation-invariant energy. For a moving contact discontinuity between a string and a smooth rigid plane in the presence of gravity, we find a surprising asymmetry between the processes of picking up and laying down, such that steady-state kinks in geometry and associated jumps in tension are not admissible during pick-up. This prediction is consistent with experimental observations. We briefly discuss related problems including the falling folded chain, peeling of an adhesive tape, and the "chain fountain". Our approach is applicable to the study of impact and locomotion, and to systems such as moored floating structures and some musical instruments that feature vibrating string and cable elements interacting with a surface.

Pathological skin picking: case presentation and review of the literature

Directory of Open Access Journals (Sweden)

Maria Isabela Sarbu

2015-04-01

Full Text Available Pathological skin picking is a condition in which patients induce skin lesions through repetitive, compulsive excoriations of normal skin or skin with minor surface irregularities and they admit their role in the production of the lesions, but are unable to stop their behavior. Psychiatric comorbidities most often associated with skin picking include obsessive-compulsive disorder (OCD, anxiety disorders, mood disorders, body dysmorphic disorders, trichotillomania and compulsive-buying disorder. We report the case of a 17 year old female patient who addressed the dermatology department of our hospital with an eruption consisting of erythematous papules and plaques. The local examination revealed several clues of paramount importance in drawing the final conclusion and the psychiatric examination helped establish the diagnosis of pathological skin picking in a patient with obsessive-compulsive disorder.

Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease

DEFF Research Database (Denmark)

Christensen, Claus Uhrenholt; Glavind, Emilie; Thomsen, Karen Louise

2018-01-01

the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol...... metabolism, inflammation, and fibrosis. RESULTS: HFHC rats developed hepatomegaly, non-fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro-inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were...... down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-α (TNFα), Interleukin (IL)-6, or IL-1β in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFα and COL1A1 mRNA expression...

Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

Energy Technology Data Exchange (ETDEWEB)

Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R. (Sanofi Aventis); (UMASS, Amherst)

2016-10-26

Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance.

Directory of Open Access Journals (Sweden)

Birgitte Holst

Full Text Available Secretory vesicles in endocrine cells store hormones such as growth hormone (GH and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs domain protein PICK1 (protein interacting with C kinase 1 as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of

Picking at waste facilities – scavenging or entrepreneurshipPicking at waste facilities – scavenging or entrepreneurship

CSIR Research Space (South Africa)

Oelofse, Suzanna HH

2010-10-01

Full Text Available Picking at landfills is a reality at most landfills in South Africa. It is often the poorest community members that resolve to picking as a way of making a living, typically under conditions that are not conducive to their health or safety. However...

White matter abnormalities in skin picking disorder

DEFF Research Database (Denmark)

Grant, Jon E; Odlaug, Brian Lawrence; Hampshire, Adam

2013-01-01

Skin picking disorder (SPD) is characterized by the repetitive and compulsive picking of skin, resulting in tissue damage. Neurocognitive findings in SPD implicate difficulty with response inhibition (suppression of pre-potent motor responses). This function is dependent on the integrity of the r......Skin picking disorder (SPD) is characterized by the repetitive and compulsive picking of skin, resulting in tissue damage. Neurocognitive findings in SPD implicate difficulty with response inhibition (suppression of pre-potent motor responses). This function is dependent on the integrity...... remarkably similar to those previously reported in trichotillomania. This study adds considerable support to the notion that-in addition to the phenomenological and comorbid overlap between SPD and trichotillomania-these disorders likely share overlapping neurobiology....

Wavefront picking for 3D tomography and full-waveform inversion

KAUST Repository

AlTheyab, Abdullah

2016-09-08

We have developed an efficient approach for picking firstbreak wavefronts on coarsely sampled time slices of 3D shot gathers. Our objective was to compute a smooth initial velocity model for multiscale full-waveform inversion (FWI). Using interactive software, first-break wavefronts were geometrically modeled on time slices with a minimal number of picks. We picked sparse time slices, performed traveltime tomography, and then compared the predicted traveltimes with the data in-between the picked slices. The picking interval was refined with iterations until the errors in traveltime predictions fell within the limits necessary to avoid cycle skipping in early arrivals FWI. This approach was applied to a 3D ocean-bottom-station data set. Our results indicate that wavefront picking has 28% fewer data slices to pick compared with picking traveltimes in shot gathers. In addition, by using sparse time samples for picking, data storage is reduced by 88%, and therefore allows for a faster visualization and quality control of the picks. Our final traveltime tomogram is sufficient as a starting model for early arrival FWI. © 2016 Society of Exploration Geophysicists.

Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion

NARCIS (Netherlands)

Jonkman, MF; Scheffer, H; Stulp, R; Pas, HH; Nijenhuis, Albertine; Heeres, K; Owaribe, K; Pulkkinen, L; Uitto, J

1997-01-01

Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene

PICK1 regulates the trafficking of ASIC1a and acidotoxicity in a BAR domain lipid binding-dependent manner

Directory of Open Access Journals (Sweden)

Jin Wenying

2010-12-01

Full Text Available Abstract Background Acid-sensing ion channel 1a (ASIC1a is the major ASIC subunit determining acid-activated currents in brain neurons. Recent studies show that ASIC1a play critical roles in acid-induced cell toxicity. While these studies raise the importance of ASIC1a in diseases, mechanisms for ASIC1a trafficking are not well understood. Interestingly, ASIC1a interacts with PICK1 (protein interacting with C-kinase 1, an intracellular protein that regulates trafficking of several membrane proteins. However, whether PICK1 regulates ASIC1a surface expression remains unknown. Results Here, we show that PICK1 overexpression increases ASIC1a surface level. A BAR domain mutant of PICK1, which impairs its lipid binding capability, blocks this increase. Lipid binding of PICK1 is also required for PICK1-induced clustering of ASIC1a. Consistent with the effect on ASIC1a surface levels, PICK1 increases ASIC1a-mediated acidotoxicity and this effect requires both the PDZ and BAR domains of PICK1. Conclusions Taken together, our results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner.

Dyslipidaemia--hepatic and intestinal cross-talk.

LENUS (Irish Health Repository)

Tomkin, Gerald H

2010-06-01

Cholesterol metabolism is tightly regulated with the majority of de novo cholesterol synthesis occurring in the liver and intestine. 3 Hydroxy-3-methylglutaryl coenzyme A reductase, a major enzyme involved in cholesterol synthesis, is raised in both liver and intestine in diabetic animals. Niemann PickC1-like1 protein regulates cholesterol absorption in the intestine and facilitates cholesterol transport through the liver. There is evidence to suggest that the effect of inhibition of Niemann PickC1-like1 lowers cholesterol through its effect not only in the intestine but also in the liver. ATP binding cassette proteins G5\\/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile. Diabetes is associated with reduced ATP binding cassette protein G5\\/G8 expression in both the liver and intestine in animal models. Microsomal triglyceride transfer protein is central to the formation of the chylomicron in the intestine and VLDL in the liver. Microsomal triglyceride transfer protein mRNA is increased in diabetes in both the intestine and liver. Cross-talk between the intestine and liver is poorly documented in humans due to the difficulty in obtaining liver biopsies but animal studies are fairly consistent in showing relationships that explain in part mechanisms involved in cholesterol homeostasis.

Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis.

Science.gov (United States)

Elrick, Matthew J; Lieberman, Andrew P

2013-02-01

Alterations in macroautophagy (hereafter referred to as "autophagy") are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction.

High frequency permeameter with semi-rigid pick-up coil

International Nuclear Information System (INIS)

Shin, Sung-Yong; Shin, Kwang-Ho . E-mail : khshin@star.ks.ac.kr; Kim, Jong-sung; Kim, Young-Hak; Lim, Sang-Ho; Sa-gong, Geon

2006-01-01

In this study, we propose the application of semi-rigid cable loop as a single turn shielded loop pick-up coil for the high frequency permeameter. Since the semi-rigid cable pick-up coil has simple structure, it is very easy to make the pick-up coil with bending and conventional soldering. The permeability of cobalt base amorphous ribbon was investigated using the developed permeameter for demonstrating its performance. The permeability of the amorphous ribbon was driven from the S-parameters measured using a network analyzer and permameter having the semi-rigid pick-up coil

Performance of diamond and point attack coal cutter picks

Energy Technology Data Exchange (ETDEWEB)

Liu, Y. [CSIRO, Brisbane, Qld. (Australia). Division of Exploration and Mining

1996-12-31

This paper presents results of laboratory experiments and field trials of PDC (Polycrystalline Diamond Compact) and PA (Point Attack) coal cutter picks. Laboratory cutting tests included linear rock and coal cutting and turning rock cutting. The following parameters were measured to assess performance of PDC and PA cutter picks: cutting force, normal force, specific energy consumption, yield, dust generation and ignitional characteristics (temperature rise). Field trials were conducted on a longwall shearer. Performance of both types of pick interims of pick life and dust generation were assessed. 3 refs., 18 figs., 3 tabs.

Analysis of Pick-Up Development in Punching

DEFF Research Database (Denmark)

Olsson, David Dam; Bay, Niels; Andreasen, Jan Lasson

2002-01-01

The development of pick-up of work piece material on the punch surface with increasing number of strokes during punching of stainless steel sheet is investigated applying Scanning Electron Microscopy (SEM), 3D roughness mapping and measurements of the backstroke force. It is found that pick...

A Proposed Analytical Model for Integrated Pick-and-Sort Systems

Directory of Open Access Journals (Sweden)

Recep KIZILASLAN

2013-11-01

Full Text Available In this study we present an analytical approach for integration of order picking and sortation operations which are the most important, labour intensive and costly activity for warehouses. Main aim is to investigate order picking and sorting efficiencies under different design issues as a function of order wave size. Integrated analytical model is proposed to estimate the optimum order picking and order sortation efficiency. The model, which has been tested by simulations with different illustrative examples, calculates the optimum wave size that solves the trade-off between picking and sorting operations and makes the order picking and sortations efficiency maximum. Our model also allow system designer to predict the order picking and sorting capacity for different system configurations. This study presents an innovative approach for integrated warehouse operations.

Excoriation (skin-picking disorder: a systematic review of treatment options

Directory of Open Access Journals (Sweden)

Lochner C

2017-07-01

Full Text Available Christine Lochner,1 Annerine Roos,1 Dan J Stein2 1SU/UCT MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, South Africa; 2SU/UCT MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Abstract: Although pathological skin-picking has been documented in the medical literature since the 19th century, it has only recently been included as a distinct entity in psychiatric classification systems. In the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposed International Classification of Diseases, Eleventh Revision, excoriation (skin-picking disorder (ED, also known as neurotic excoriation, psychogenic excoriation, or dermatillomania, is described as recurrent picking of skin, leading to skin lesions and significant distress or functional impairment. ED is listed as one of the obsessive–compulsive and related disorders, given its overlap with conditions such as trichotillomania (hair-pulling disorder. Arguably, its inclusion and delineation in the diagnostic nomenclature will lead to increased awareness of the condition, more research, and ultimately in treatment advances. This systematic review aims to provide readers with an up-to-date view of current treatment options for ED. A MEDLINE search of the ED treatment literature was conducted to collate relevant articles published between 1996 and 2017. The findings indicate that a number of randomized controlled trails on ED have now been published, and that current management options include behavioral therapy (habit reversal or acceptance-enhanced behavior therapy, and medication (selective serotonin reuptake inhibitors or N-acetyl cysteine. Keywords: excoriation, skin-picking, treatment, habit reversal therapy, behavioral therapy, pharmacotherapy, systematic review

Quantifying low-frequency revertants in oral poliovirus vaccine using next generation sequencing.

Science.gov (United States)

Sarcey, Eric; Serres, Aurélie; Tindy, Fabrice; Chareyre, Audrey; Ng, Siemon; Nicolas, Marine; Vetter, Emmanuelle; Bonnevay, Thierry; Abachin, Eric; Mallet, Laurent

2017-08-01

Spontaneous reversion to neurovirulence of live attenuated oral poliovirus vaccine (OPV) serotype 3 (chiefly involving the n.472U>C mutation), must be monitored during production to ensure vaccine safety and consistency. Mutant analysis by polymerase chain reaction and restriction enzyme cleavage (MAPREC) has long been endorsed by the World Health Organization as the preferred in vitro test for this purpose; however, it requires radiolabeling, which is no longer supported by many laboratories. We evaluated the performance and suitability of next generation sequencing (NGS) as an alternative to MAPREC. The linearity of NGS was demonstrated at revertant concentrations equivalent to the study range of 0.25%-1.5%. NGS repeatability and intermediate precision were comparable across all tested samples, and NGS was highly reproducible, irrespective of sequencing platform or analysis software used. NGS was performed on OPV serotype 3 working seed lots and monovalent bulks (n=21) that were previously tested using MAPREC, and which covered the representative range of vaccine production. Percentages of 472-C revertants identified by NGS and MAPREC were comparable and highly correlated (r≥0.80), with a Pearson correlation coefficient of 0.95585 (p<0.0001). NGS demonstrated statistically equivalent performance to that of MAPREC for quantifying low-frequency OPV serotype 3 revertants, and offers a valid alternative to MAPREC. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Expression patterns of sterol transporters NPC1 and NPC2 in the cnidarian-dinoflagellate symbiosis.

Science.gov (United States)

Dani, Vincent; Priouzeau, Fabrice; Mertz, Marjolijn; Mondin, Magali; Pagnotta, Sophie; Lacas-Gervais, Sandra; Davy, Simon K; Sabourault, Cécile

2017-10-01

The symbiotic interaction between cnidarians (e.g., corals and sea anemones) and photosynthetic dinoflagellates of the genus Symbiodinium is triggered by both host-symbiont recognition processes and metabolic exchange between the 2 partners. The molecular communication is crucial for homeostatic regulation of the symbiosis, both under normal conditions and during stresses that further lead to symbiosis collapse. It is therefore important to identify and fully characterise the key players of this intimate interaction at the symbiotic interface. In this study, we determined the cellular and subcellular localization and expression of the sterol-trafficking Niemann-Pick type C proteins (NPC1 and NPC2) in the symbiotic sea anemones Anemonia viridis and Aiptasia sp. We first established that NPC1 is localised within vesicles in host tissues and to the symbiosome membranes in several anthozoan species. We demonstrated that the canonical NPC2-a protein is mainly expressed in the epidermis, whereas the NPC2-d protein is closely associated with symbiosome membranes. Furthermore, we showed that the expression of the NPC2-d protein is correlated with symbiont presence in healthy symbiotic specimens. As npc2-d is a cnidarian-specific duplicated gene, we hypothesised that it probably arose from a subfunctionalisation process that might result in a gain of function and symbiosis adaptation in anthozoans. Niemann-Pick type C proteins may be key players in a functional symbiosis and be useful tools to study host-symbiont interactions in the anthozoan-dinoflagellate association. © 2017 John Wiley & Sons Ltd.

Warehouse Order-Picking Process. Review

Directory of Open Access Journals (Sweden)

E. V. Korobkov

2015-01-01

Full Text Available This article describes basic warehousing activities, namely: movement, information storage and transfer, as well as connections between typical warehouse operations (reception, transfer, assigning storage position and put-away, order-picking, hoarding and sorting, cross-docking, shipping. It presents a classification of the warehouse order-picking systems in terms of manual labor on offer as well as external (marketing channels, consumer’s demand structure, supplier’s replenishment structure and inventory level, total production demand, economic situation and internal (mechanization level, information accessibility, warehouse dimensionality, method of dispatch for shipping, zoning, batching, storage assignment method, routing method factors affecting the designing systems complexity. Basic optimization considerations are described. There is a literature review on the following sub-problems of planning and control of orderpicking processes.A layout design problem has been taken in account at two levels — external (facility layout problem and internal (aisle configuration problem. For a problem of distributing goods or stock keeping units the following methods are emphasized: random, nearest open storage position, and dedicated (COI-based, frequency-based distribution, as well as class-based and familygrouped (complimentary- and contact-based one. Batching problem can be solved by two main methods, i.e. proximity order batching (seed and saving algorithms and time-window order batching. There are two strategies for a zoning problem: progressive and synchronized, and also a special case of zoning — bucket brigades method. Hoarding/sorting problem is briefly reviewed. Order-picking routing problem will be thoroughly described in the next article of the cycle “Warehouse order-picking process”.

Herbert L. Pick Jr. (1930-2012).

Science.gov (United States)

Rieser, John J; Lockman, Jeffrey J

2013-01-01

Presents an obituary for Herbert L. Pick Jr. For 49 years at the University of Minnesota's Institute of Child Development, new students were often greeted by an unassuming guy who rode to work on his bike, helped them carry boxes of books to their offices, and turned out to be a famous professor. Herbert L. Pick Jr. was a fabulous mentor, teacher, and developmental scientist. His work on perception and perceptual development spanned basic and applied science, laboratory and real-world settings. He was honored with the Division 7 (Developmental Psychology) Mentor Award from the American Psychological Association in 1998. He was honored again in 2002, jointly with his wife Anne D. Pick, with a volume of the Minnesota Symposium on Child Psychology based on a central theme of their work and titled "Action as an Organizer of Learning and Development." Two weeks before his death he was honored yet again with a Festschrift titled "Realism to Relevance: An Ecological Approach to Perception, Action and Cognition." Former students and academic admirers gave talks focused on the scientific themes Herb championed, namely, effects of experience on learning and development, organism-environment fit, environmental structure, and societal applications of research about basic psychological processes. He gave the final talk, and after thanking everyone in his typically humble way, he discussed his new research on visual-locomotor coordination. Herb died on June 18, 2012. He is greatly missed by Anne, his wife of 50 years; his sister Barbara; his daughters (and their husbands) Cindy (Jon), Karen (John), and Gretchen (Michael); and his grandchildren Alex, Ted, Katy, Joe, Eva, Sam, Rowan, and Culley. He is also missed by his many students, colleagues, friends, and admirers.

The relationship of psychological trauma with trichotillomania and skin picking.

Science.gov (United States)

Özten, Eylem; Sayar, Gökben Hızlı; Eryılmaz, Gül; Kağan, Gaye; Işık, Sibel; Karamustafalıoğlu, Oğuz

2015-01-01

Interactions between psychological, biological and environmental factors are important in development of trichotillomania and skin picking. The aim of this study is to determine the relationship of traumatic life events, symptoms of post-traumatic stress disorder and dissociation in patients with diagnoses of trichotillomania and skin picking disorder. The study included patients who was diagnosed with trichotillomania (n=23) or skin picking disorder (n=44), and healthy controls (n=37). Beck Depression Inventory, Traumatic Stress Symptoms Scale and Dissociative Experiences Scale were administered. All groups checked a list of traumatic life events to determine the exposed traumatic events. There was no statistical significance between three groups in terms of Dissociative Experiences Scale scores (P=0.07). But Beck Depression Inventory and Traumatic Stress Symptoms Scale scores of trichotillomania and skin picking groups were significantly higher than the control group. Subjects with a diagnosis of trichotillomania and skin picking reported statistically significantly higher numbers of traumatic and negative events in childhood compared to healthy subjects. We can conclude that trauma may play a role in development of both trichotillomania and skin picking. Increased duration of trichotillomania or skin picking was correlated with decreased presence of post-traumatic stress symptoms. The reason for the negatively correlation of severity of post-traumatic stress symptoms and self-harming behavior may be speculated as developing trichotillomania or skin picking symptoms helps the patient to cope with intrusive thoughts related to trauma. Future longitudinal research must focus on whether trauma and post-traumatic stress or trichotillomania and skin picking precede the development of mental disorder.

Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.

Directory of Open Access Journals (Sweden)

Sarah R Pigozzo

Full Text Available Muscles in Duchenne dystrophy patients are characterized by the absence of dystrophin, yet transverse sections show a small percentage of fibers (termed "revertant fibers" positive for dystrophin expression. This phenomenon, whose biological bases have not been fully elucidated, is present also in the murine and canine models of DMD and can confound the evaluation of therapeutic approaches. We analyzed 11 different muscles in a cohort of 40 mdx mice, the most commonly model used in pre-clinical studies, belonging to four age groups; such number of animals allowed us to perform solid ANOVA statistical analysis. We assessed the average number of dystrophin-positive fibers, both absolute and normalized for muscle size, and the correlation between their formation and the ageing process. Our results indicate that various muscles develop different numbers of revertant fibers, with different time trends; besides, they suggest that the biological mechanism(s behind dystrophin re-expression might not be limited to the early development phases but could actually continue during adulthood. Importantly, such finding was seen also in cardiac muscle, a fact that does not fit into the current hypothesis of the clonal origin of "revertant" myonuclei from satellite cells. This work represents the largest, statistically significant analysis of revertant fibers in mdx mice so far, which can now be used as a reference point for improving the evaluation of therapeutic approaches for DMD. At the same time, it provides new clues about the formation of revertant fibers/cardiomyocytes in dystrophic skeletal and cardiac muscle.

Fast and Reliable Mouse Picking Using Graphics Hardware

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Hanli Zhao

2009-01-01

Full Text Available Mouse picking is the most commonly used intuitive operation to interact with 3D scenes in a variety of 3D graphics applications. High performance for such operation is necessary in order to provide users with fast responses. This paper proposes a fast and reliable mouse picking algorithm using graphics hardware for 3D triangular scenes. Our approach uses a multi-layer rendering algorithm to perform the picking operation in linear time complexity. The objectspace based ray-triangle intersection test is implemented in a highly parallelized geometry shader. After applying the hardware-supported occlusion queries, only a small number of objects (or sub-objects are rendered in subsequent layers, which accelerates the picking efficiency. Experimental results demonstrate the high performance of our novel approach. Due to its simplicity, our algorithm can be easily integrated into existing real-time rendering systems.

Design and Control of Warehouse Order Picking: a literature review

NARCIS (Netherlands)

M.B.M. de Koster (René); T. Le-Duc (Tho); K.J. Roodbergen (Kees-Jan)

2006-01-01

textabstractOrder picking has long been identified as the most labour-intensive and costly activity for almost every warehouse; the cost of order picking is estimated to be as much as 55% of the total warehouse operating expense. Any underperformance in order picking can lead to unsatisfactory

NOISY DISPERSION CURVE PICKING (NDCP): a Matlab friendly suite package for fully control dispersion curve picking

Science.gov (United States)

Granados, I.; Calo, M.; Ramos, V.

2017-12-01

We developed a Matlab suite package (NDCP, Noisy Dispersion Curve Picking) that allows a full control over parameters to identify correctly group velocity dispersion curves in two types of datasets: correlograms between two stations or surface wave records from earthquakes. Using the frequency-time analysis (FTAN), the procedure to obtain the dispersion curves from records with a high noise level becomes difficult, and sometimes, the picked curve result in a misinterpreted character. For correlogram functions, obtained with cross-correlation of noise records or earthquake's coda, a non-homogeneous noise sources distribution yield to a non-symmetric Green's function (GF); to retrieve the complete information contained in there, NDCP allows to pick the dispersion curve in the time domain both in the causal and non-causal part of the GF. Then the picked dispersion curve is displayed on the FTAN diagram to in order to check if it matches with the maximum of the signal energy avoiding confusion with overtones or spike of noise. To illustrate how NDCP performs, we show exemple using: i) local correlograms functions obtained from sensors deployed into a volcanic caldera (Los Humeros, in Puebla, Mexico), ii) regional correlograms functions between two stations of the National Seismological Service (SSN, Servicio Sismológico Nacional in Spanish), and iii) surface wave seismic record for an earthquake located in the Pacific Ocean coast of Mexico and recorded by the SSN. This work is supported by the GEMEX project (Geothermal Europe-Mexico consortium).

The relationship between adolescents' academic stress, impulsivity, anxiety, and skin picking behavior.

Science.gov (United States)

Yeo, Sun Kyung; Lee, Woo Kyeong

2017-08-01

Skin picking behavior involves an individual picking or biting their skin repeatedly. Although this behavior commonly occurs at a young age, little research has addressed its harmful effects among the Korean population. Therefore, we examined the characteristics of South Korean adolescents who reported skin picking behavior. South Korean students aged 12-16 years participated (N=410, females=52.2%). They completed questionnaires that addressed skin picking behavior, academic stress, impulsivity, and anxiety. The survey was conducted in Seoul and Gyeonggi-do from February-March 2016. Among participants, 66.8% reported that they had picked their skin and 15.4% did so currently. Skin picking was positively correlated with academic stress, impulsivity, and anxiety. Students who picked their skin more often displayed more anxiety, academic stress, and impulsivity. Future studies should address skin picking adolescents' characteristics, especially regarding anxiety and academic stress. Educational programs should be implemented to help adolescents decrease their anxiety and academic stress and prevent the worsening of skin picking behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy.

Science.gov (United States)

Levi, Oshrat; Genin, Olga; Angelini, Corrado; Halevy, Orna; Pines, Mark

2015-09-15

Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3-9 years) an inverse correlation was observed between the levels of collagen type I - representing fibrosis - and the levels of utrophin. This correlation was independent of the patient's age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius. In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis.

Order Picking Optimization in Carousels Storage System

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Xiong-zhi Wang

2013-01-01

Full Text Available This paper addresses the order picking problem in a material handling system consisting of multiple carousels and one picker. Carousels are rotatable closed-loop storage systems for small items, where items are stored in bins along the loop. An order at carousels consists of n different items stored there. The objective is to find an optimal picking sequence to minimizing the total order picking time. After proving the problem to be strongly NP-hard and deriving two characteristics, we develop a dynamic programming algorithm (DPA for a special case (two-carousel storage system and an improved nearest items heuristics (INIH for the general problem. Experimental results verify that the solutions are quickly and steadily achieved and show their better performance.

The impact of COI-based storage on order-picking times

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Grzegorz Tarczyński

2017-09-01

Full Text Available Background: The increasing competitiveness on the global markets enforces the need for a fast and reliable delivery. This task is possible to perform by improving the order-picking systems. The implementation of automated storage and retrieval systems (AS/RS is not always profitable. In the warehouses where the order-picking is performed in accordance with the principle of picker-to-part rule, the picking efficiency optimization includes among others: the warehouse layout, the storage policy, the routing heuristic, the way of zoning, the order-batching method, and the sequencing of pick-lists. In the paper the impact of the storage policy on the order-picking times is checked. Methods: The influence of storage based on Heskett’s cube-per-order index (COI on the average order-picking times is analyzed. The items based on increasing values of COI index are divided on classes. To determine the demand for items the analytical function proposed by Caron is used. Results: In the paper the benefits of storage based on COI index are compared with random storage and storage based only on picking frequency. It is assumed that the bin, to which the picker collects items has limited capacity – some orders has to be divided on smaller pick-lists. The analysis was performed using simulation tools. Additionally, the algorithm (taking into account different sizes of picker’s bin for order-batching is presented. Conclusions: The analysis shows that the COI-based storage is particularly effective when the size of items increases. The COI-based curve is less skewed than the curve based only on picking frequency. The choice of storage policy should be carried out together with routing heuristic. The use of batching algorithm significantly increases the effectiveness of the order-picking process, but the optimal size of picker’s bin (and batch should be optimized with consideration the sorting process.

Bayesian Peak Picking for NMR Spectra

KAUST Repository

Cheng, Yichen

2014-02-01

Protein structure determination is a very important topic in structural genomics, which helps people to understand varieties of biological functions such as protein-protein interactions, protein–DNA interactions and so on. Nowadays, nuclear magnetic resonance (NMR) has often been used to determine the three-dimensional structures of protein in vivo. This study aims to automate the peak picking step, the most important and tricky step in NMR structure determination. We propose to model the NMR spectrum by a mixture of bivariate Gaussian densities and use the stochastic approximation Monte Carlo algorithm as the computational tool to solve the problem. Under the Bayesian framework, the peak picking problem is casted as a variable selection problem. The proposed method can automatically distinguish true peaks from false ones without preprocessing the data. To the best of our knowledge, this is the first effort in the literature that tackles the peak picking problem for NMR spectrum data using Bayesian method.

Automatic microseismic event picking via unsupervised machine learning

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Chen, Yangkang

2018-01-01

Effective and efficient arrival picking plays an important role in microseismic and earthquake data processing and imaging. Widely used short-term-average long-term-average ratio (STA/LTA) based arrival picking algorithms suffer from the sensitivity to moderate-to-strong random ambient noise. To make the state-of-the-art arrival picking approaches effective, microseismic data need to be first pre-processed, for example, removing sufficient amount of noise, and second analysed by arrival pickers. To conquer the noise issue in arrival picking for weak microseismic or earthquake event, I leverage the machine learning techniques to help recognizing seismic waveforms in microseismic or earthquake data. Because of the dependency of supervised machine learning algorithm on large volume of well-designed training data, I utilize an unsupervised machine learning algorithm to help cluster the time samples into two groups, that is, waveform points and non-waveform points. The fuzzy clustering algorithm has been demonstrated to be effective for such purpose. A group of synthetic, real microseismic and earthquake data sets with different levels of complexity show that the proposed method is much more robust than the state-of-the-art STA/LTA method in picking microseismic events, even in the case of moderately strong background noise.

Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

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Keiichi Motoyama

2015-11-01

Full Text Available The Niemann–Pick type C disease (NPC is one of inherited lysosomal storage disorders, emerges the accumulation of unesterified cholesterol in endolysosomes. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD has been applied for the treatment of NPC. HP-β-CyD improved hepatosplenomegaly in NPC patients, however, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by actively targeted-β-CyD to hepatocytes is expected. In the present study, to deliver β-CyD selectively to hepatocytes, we newly fabricated mono-lactose-appended β-CyD (Lac-β-CyD and evaluated its cholesterol lowering effects in NPC-like HepG2 cells, cholesterol accumulated HepG2 cells induced by treatment with U18666A. Lac-β-CyD (degree of substitution of lactose (DSL 1 significantly decreased the intracellular cholesterol content in a concentration-dependent manner. TRITC-Lac-β-CyD was associated with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR-mediated endocytosis and decreased the accumulation of intracellular cholesterol in NPC-like HepG2 cells. These results suggest that Lac-β-CyD may have the potential as a drug for the treatment of hepatosplenomegaly in NPC disease.

Performance approximation of pick-to-belt orderpicking systems

NARCIS (Netherlands)

M.B.M. de Koster (René)

1994-01-01

textabstractIn this paper, an approximation method is discussed for the analysis of pick-to-belt orderpicking systems. The aim of the approximation method is to provide an instrument for obtaining rapid insight in the performance of designs of pick-to-belt orderpicking systems. It can be used to

Selective visualization of fluorescent sterols in Caenorhabditis elegans by bleach-rate-based image segmentation

DEFF Research Database (Denmark)

Wüstner, Daniel; Landt Larsen, Ane; Færgeman, Nils J.

2010-01-01

The nematode Caenorhabditis elegans is a genetically tractable model organism to investigate sterol transport. In vivo imaging of the fluorescent sterol, dehydroergosterol (DHE), is challenged by C. elegans' high autofluorescence in the same spectral region as emission of DHE. We present a method....... Bleach-rate constants were determined for DHE in vivo and confirmed in model membranes. Using this method, we could detect enrichment of DHE in specific tissues like the nerve ring, the spermateca and oocytes. We confirm these results in C. elegans gut-granule-loss (glo) mutants with reduced...... homologues of Niemann-Pick C disease proteins. Our approach is generally useful for identifying fluorescent probes in the presence of high cellular autofluorescence....

Thermoresistant revertants of an Escherichia coli strain carrying tif-1 and ruv mutations: non-suppressibility of ruv by sfi

International Nuclear Information System (INIS)

Otsuji, N.; Iyehara-Ogawa, H.

1979-01-01

Spontaneous thermoresistant revertants were isolated from Tif1 Ruv - and Tif1 Ruv + strains of Escherichia coli K-12. They were divided into five groups; backmutants to tif + and recA structural gene mutants accounted for at least two of these groups. Mutations with an unconditional RecA - phenotype were detected at a higher frequency in the Tif1 Ruv - strains (65%) than in the Tif1 Ruv + strains (25%). A third group consisted of revertants exhibiting a RecA - phenotype at low temperature. Revertants with normal recombination ability and uv resistance, but with a thermosensitive defect in propagating lambda bio11 phage, were also isolated (group 4). The alleles responsible for this property were cotransducible with the srl gene, suggesting that they are located at the recA locus. Other revertants, which might carry lexA, lexB, or zab mutations, were uv sensitive and were able to propagate lambda bio11 phage (group 5). The sfi mutation, which suppresses filamentation in the Tif1 and uv-sensitive Lon - strains, does not restore uv resistance of the Ruv - mutant

The relationship of psychological trauma with trichotillomania and skin picking

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Özten E

2015-05-01

Full Text Available Eylem Özten,1 Gökben Hızlı Sayar,1 Gül Eryilmaz,1 Gaye Kağan,2 Sibel Işik,3 Oğuz Karamustafalioğlu4 1Neuropsychiatry Health, Practice, and Research Center, Üsküdar University, 2Istanbul Neuropsychiatry Hospital, Üsküdar University, 3Turkish Red Crescent Altintepe Medical Center, 4Department of Psychology, Faculty of Human and Social Sciences, Üsküdar University, Istanbul, Turkey Objective: Interactions between psychological, biological and environmental factors are important in development of trichotillomania and skin picking. The aim of this study is to determine the relationship of traumatic life events, symptoms of post-traumatic stress disorder and dissociation in patients with diagnoses of trichotillomania and skin picking disorder.Methods: The study included patients who was diagnosed with trichotillomania (n=23 or skin picking disorder (n=44, and healthy controls (n=37. Beck Depression Inventory, Traumatic Stress Symptoms Scale and Dissociative Experiences Scale were administered. All groups checked a list of traumatic life events to determine the exposed traumatic events.Results: There was no statistical significance between three groups in terms of Dissociative Experiences Scale scores (P=0.07. But Beck Depression Inventory and Traumatic Stress Symptoms Scale scores of trichotillomania and skin picking groups were significantly higher than the control group. Subjects with a diagnosis of trichotillomania and skin picking reported statistically significantly higher numbers of traumatic and negative events in childhood compared to healthy subjects.Conclusion: We can conclude that trauma may play a role in development of both trichotillomania and skin picking. Increased duration of trichotillomania or skin picking was correlated with decreased presence of post-traumatic stress symptoms. The reason for the negatively correlation of severity of post-traumatic stress symptoms and self-harming behavior may be speculated as

Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A2A Receptor in Hippocampal Glutamate Synapses.

Science.gov (United States)

Machado, Nuno J; Simões, Ana Patrícia; Silva, Henrique B; Ardais, Ana Paula; Kaster, Manuella P; Garção, Pedro; Rodrigues, Diana I; Pochmann, Daniela; Santos, Ana Isabel; Araújo, Inês M; Porciúncula, Lisiane O; Tomé, Ângelo R; Köfalvi, Attila; Vaugeois, Jean-Marie; Agostinho, Paula; El Yacoubi, Malika; Cunha, Rodrigo A; Gomes, Catarina A

2017-03-01

Caffeine prophylactically prevents mood and memory impairments through adenosine A 2A receptor (A 2A R) antagonism. A 2A R antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher A 2A R density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A 2A R agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A 2A R antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A 2A R controlling synaptic glutamatergic function.

Automatic first-break picking using the instantaneous traveltime attribute

KAUST Repository

Saragiotis, Christos; Alkhalifah, Tariq Ali

2012-01-01

Picking the first breaks is an important step in seismic processing. The large volume of the seismic data calls for automatic and objective picking. We introduce a new automatic first-break picker, which uses specifically designed time windows

Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.

Science.gov (United States)

Krawczyk, Marcin; Lütjohann, Dieter; Schirin-Sokhan, Ramin; Villarroel, Luis; Nervi, Flavio; Pimentel, Fernando; Lammert, Frank; Miquel, Juan Francisco

2012-05-01

In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol

Using the Min/Max Method for Replenishment of Picking Locations

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Apsalons Raitis

2017-03-01

Full Text Available The irregularity of removing quantities from a definite picking location in a warehouse very often results in the stock out in the particular picking address. In practice, the Red Card principle is used to determine a critical level for each picking location when it is necessary to start the replenishment of stock in the picking address. The question is how to calculate an adequate critical level. The guidelines in this paper explain in detail the solution of the problem using the Min/Max stock control method and mathematical algorithms adjusted by authors. In order to check the validity of these mathematical algorithms of the Min/Max method, the simulation modelling has been also done and presented.

Assignment of stock keeping units to parallel undirectional picking

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Matthews, Jason

2015-05-01

Full Text Available An order picking system consisting of a number of parallel unidirectional picking lines is investigated. Stock keeping units (SKUs that are grouped by product type into distributions (DBNs are assigned daily to available picking lines. A mathematical programming formulation and its relaxations is presented. A greedy insertion and a greedy phased insertion are further introduced to obtain feasible results within usable computation times for all test cases. The walking distance of the pickers was shown to decrease by about 22 per cent compared with the current assignment approach. However, product handling and operational risk increases.

Adaptive Motion Planning in Bin-Picking with Object Uncertainties

DEFF Research Database (Denmark)

Iversen, Thomas Fridolin; Ellekilde, Lars-Peter; Miró, Jaime Valls

2017-01-01

Doing motion planning for bin-picking with object uncertainties requires either a re-grasp of picked objects or an online sensor system. Using the latter is advantageous in terms of computational time, as no time is wasted doing an extra pick and place action. It does, however, put extra...... requirements on the motion planner, as the target position may change on-the-fly. This paper solves that problem by using a state adjusting Partial Observable Markov Decision Process, where the state space is modified between runs, to better fit earlier solved problems. The approach relies on a set...

Investigation on the crystallography of the transformation products of reverted austenite in intercritically reheated coarse grained heat affected zone

International Nuclear Information System (INIS)

You, Yang; Shang, Chengjia; Chen, Liang; Subramanian, Sundaresa

2013-01-01

Highlights: ► Area of reverted austenite is traced out by crystallographic information. ► Bainite and martensite regions were confirmed within it. ► The martensite region is considered as the blocky MA particles. ► Martensite region has high deformation to initiate fracture. ► More uniform transformation of the reverted austenite is good for toughness. -- Abstract: In present study the intercritically reheated coarse grained heat affected zone (ICCGHAZ) showing the worst impact toughness in the heat affected zone of multi-pass welding was simulated by Gleeble-1500, and its microstructure was investigated in detail by means of scanning electron microscope (SEM) and electron backscattering diffraction (EBSD). With the crystallographic information from EBSD scanning the area of a single reverted austenite grain which formed during the thermal cycles of second pass simulation was traced out. Within it two regions with different characteristic both in morphology and crystallography were found out, showing an un-uniform transformation of the reverted austenite. The region I is a bainitic region containing larger bainitic ferrite grains, while the region II is made up of several clusters containing tiny grains. Based on the crystallographic information each cluster was determined as martensite island thereby should be considered as blocky Martensite/Austenite constituent (M/A), which is hard phase and harmful for toughness. Analysis on the level of deformation shows that the region II is much higher deformed than the region I, indicating there is high stress concentration within the region II. The possible influence of the region I and the region II on fracture is discussed under the early proposed M/A’s fracture-initiating mechanisms. It suggests that the main cause of the toughness reduction is the un-uniform transformation of the reverted austenite, and the toughness performance of the ICCGHAZ could be improved if the transformation of the reverted

Methodology of Evaluation of the Impact of Picking Area Location on the Total Costs of Warehouse

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Apsalons Raitis

2017-12-01

Full Text Available The picking system and the layout of the picking area are the key drivers for the evaluation of a warehouse picking cost. There are five variants for organizing the picking process of orders in a warehouse. The choice of a specific variant depends on the total cost of picking. The picking cost is evaluated within an uninterrupted picking process. It means that no stock out occurs in the time period of the picking process. The storing area and the picking area are created as two separate zones for picking quantities of the customer’s orders; the principle of division of orders is observed strictly. Referring to the locations of stock keeping units (SKU, two approaches of the layout of SKU in the picking area can be estimated. The first one is the single picking location for each single SKU, where replenishment is realized in the picking process. The second one - various picking locations for each single SKU, and the replenishment here is realized just only prior to a picking process or after it. The main benefits of the economy of the picking cost as far as these two approaches are concerned are the shortest picking route in the first case and one common replenishment option in the second case.

Aligning Order Picking Methods, Incentive Systems, and Regulatory Focus to Increase Performance

NARCIS (Netherlands)

de Vries, J.; de Koster, R.; Stam, D.

2016-01-01

A controlled field experiment investigates order picking performance in terms of productivity. We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems (competition-based vs. cooperation-based) for pickers with

Aligning order picking methods, incentive systems, and regulatory focus to increase performance

NARCIS (Netherlands)

J. de Vries (Jelle); M.B.M. de Koster (René); D.A. Stam (Daan)

2015-01-01

textabstractA unique controlled field experiment investigates order picking performance (in terms of productivity and quality). We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems (competition- based versus

Excoriation (skin-picking) disorder in adults

DEFF Research Database (Denmark)

Leibovici, Vera; Koran, Lorrin M; Murad, Sari

2015-01-01

OBJECTIVE: We sought to estimate the lifetime prevalence of Excoriation (Skin-Picking) Disorder (SPD) in the Israeli adult population as a whole and compare SPD prevalence in the Jewish and Arab communities. We also explored demographic, medical and psychological correlates of SPD diagnosis. METH......-reported medical and psychiatric comorbidities between the Jewish and Arab subsamples suggest the possibility of cross-cultural variation in the correlates of this disorder.......OBJECTIVE: We sought to estimate the lifetime prevalence of Excoriation (Skin-Picking) Disorder (SPD) in the Israeli adult population as a whole and compare SPD prevalence in the Jewish and Arab communities. We also explored demographic, medical and psychological correlates of SPD diagnosis...

Estimating order-picking times for return heuristic - equations and simulations

Directory of Open Access Journals (Sweden)

Grzegorz Tarczyński

2015-09-01

Full Text Available Background: A key element of the evaluation of warehouse operation is the average order-picking time. In warehouses where the order-picking process is carried out according to the "picker-to-part" rule the order-picking time is usually proportional to the distance covered by the picker while picking items. This distance can by estimated by simulations or using mathematical equations. In the paper only the best described in the literature one-block rectangular warehouses are considered. Material and methods: For the one-block rectangular warehouses there are well known five routing heuristics. In the paper the author considers the return heuristic in two variants. The paper presents well known Hall's and De Koster's equations for the average distance traveled by the picker while completing items from one pick list. The author presents own proposals for calculating the expected distance. Results: the results calculated by the use of mathematical equations (the formulas of Hall, De Koster and own propositions were compared with the average values obtained using computer simulations. For the most cases the average error does not exceed 1% (except for Hall's equations. To carry out simulation the computer software Warehouse Real-Time Simulator was used. Conclusions: the order-picking time is a function of many variables and its optimization is not easy. It can be done in two stages: firstly using mathematical equations the set of the potentially best variants is established, next the results are verified using simulations. The results calculated by the use of equations are not precise, but possible to achieve immediately. The simulations are more time-consuming, but allow to analyze the order-picking process more accurately.

The assessment of skin picking in adolescence: psychometric properties of the Skin Picking Scale-Revised (German version).

Science.gov (United States)

Gallinat, Christina; Keuthen, Nancy J; Stefini, Annette; Backenstrass, Matthias

2017-02-01

Skin picking disorder has received growing attention since the release of DSM-5, yet there are no evidence-based assessment instruments for adolescent samples. The present study examines the psychometric properties of the Skin Picking Scale-Revised (SPS-R, German version) in adolescents. A total of 76 adolescents (96% female) completed the SPS-R, the Clinical Psychological Diagnostic System (KPD-38), and a questionnaire assessing demographics and clinical characteristics online. The SPS-R had high internal consistency (α = 0.89) and significant small-to-medium correlations with reduced competence skills, psychological impairment, general life satisfaction, social support, and social problems on the KPD-38. Similar to prior findings for adults, an exploratory factor analysis suggested a two-factor model for the SPS-R in adolescents. Group comparisons failed to show significant differences on SPS-R scores between participants with and without dermatological conditions. The current results suggest that the SPS-R can be useful in adolescent samples as a reliable and valid instrument for the assessment of skin picking severity. Future research investigating scale validity and factor structure in a clinical sample of adolescent skin pickers is warranted.

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Directory of Open Access Journals (Sweden)

Fabian Arenas

2017-11-01

Full Text Available Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD, however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

PICK1 expression in the Drosophila central nervous system primarily occurs in the neuroendocrine system

DEFF Research Database (Denmark)

Jansen, Anna M; Nässel, Dick R; Madsen, Kenneth L

2009-01-01

in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1...... (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically...... neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells...

Close up of the pick and place tool carrying a dummy silicon sensor.

CERN Multimedia

Bernd Surrow

1999-01-01

The gantry positioning head contains a vacuum pick-up system thatallows several different pick-up tools to be used. This one isdesigned to pick up the silicon sensors. The pick-up tool containsa pressure sensitive contact which can stop the motion of the machine when the tool touches a fixed object. The shiny cylinderis the end of the microscope optics of the CCD camera.

Investor Outlook: Gene Therapy Picking up Steam; At a Crossroads.

Science.gov (United States)

Schimmer, Joshua; Breazzano, Steven

2016-09-01

The gene therapy field continues to pick up steam with recent successes in a number of different therapeutic indications that highlight the potential for the platform. As the field continues to make progress, a growing data set of long-term safety and efficacy data will continue to define gene therapy's role, determining ultimately how widely it may be used beyond rare, serious diseases with high unmet needs. New technologies often take unanticipated twists and turns as patient exposure accumulates, and gene therapy may be no exception. That said, with many diseases that have no other treatment options beyond gene therapy and that present considerable morbidity and mortality, the field appears poised to withstand some minor and even major bumps in the road should they emerge.

A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing

DEFF Research Database (Denmark)

Thomas Danielsen, E.; E. Møller, Morten; Yamanaka, Naoki

2016-01-01

Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis...... and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition...... and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms...

Lysosomal degradation of membrane lipids.

Science.gov (United States)

Kolter, Thomas; Sandhoff, Konrad

2010-05-03

The constitutive degradation of membrane components takes place in the acidic compartments of a cell, the endosomes and lysosomes. Sites of lipid degradation are intralysosomal membranes that are formed in endosomes, where the lipid composition is adjusted for degradation. Cholesterol is sorted out of the inner membranes, their content in bis(monoacylglycero)phosphate increases, and, most likely, sphingomyelin is degraded to ceramide. Together with endosomal and lysosomal lipid-binding proteins, the Niemann-Pick disease, type C2-protein, the GM2-activator, and the saposins sap-A, -B, -C, and -D, a suitable membrane lipid composition is required for degradation of complex lipids by hydrolytic enzymes. Copyright 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Energy-Saving Melting and Revert Reduction Technology (E-SMARRT): Final Summary Report

Energy Technology Data Exchange (ETDEWEB)

White, Thornton C [SCRA Appiled R& D

2014-03-31

Energy-Saving Melting and Revert Reduction Technology (E-SMARRT) is a balanced portfolio of R&D tasks that address energy-saving opportunities in the metalcasting industry. E-SMARRT was created to: • Improve important capabilities of castings • Reduce carbon footprint of the foundry industry • Develop new job opportunities in manufacturing • Significantly reduce metalcasting process energy consumption and includes R&D in the areas of: • Improvements in Melting Efficiency • Innovative Casting Processes for Yield Improvement/Revert Reduction • Instrumentation and Control Improvement • Material properties for Casting or Tooling Design Improvement The energy savings and process improvements developed under E-SMARRT have been made possible through the unique collaborative structure of the E-SMARRT partnership. The E-SMARRT team consisted of DOE’s Office of Industrial Technology, the three leading metalcasting technical associations in the U.S: the American Foundry Society; the North American Die Casting Association; and the Steel Founders’ Society of America; and SCRA Applied R&D, doing business as the Advanced Technology Institute (ATI), a recognized leader in distributed technology management. This team provided collaborative leadership to a complex industry composed of approximately 2,000 companies, 80% of which employ less than 100 people, and only 4% of which employ more than 250 people. Without collaboration, these new processes and technologies that enable energy efficiencies and environment-friendly improvements would have been slow to develop and had trouble obtaining a broad application. The E-SMARRT R&D tasks featured low-threshold energy efficiency improvements that are attractive to the domestic industry because they do not require major capital investment. The results of this portfolio of projects are significantly reducing metalcasting process energy consumption while improving the important capabilities of metalcastings. Through June

Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

Directory of Open Access Journals (Sweden)

Yusuke Echigoya

Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

User's guide to REVERT. A CDC 7600 program for converting Spent Fuel Test - Climax data to engineering units, with corrections

International Nuclear Information System (INIS)

Hage, G.

1984-10-01

A CDC 7600 computer program, REVERT, can revise Spent Fuel Test - Climax data files using one of several algorithms, depending on the type of data. The algorithms use coefficients from a separate file organized by data type identifiers. REVERT can also make that file of coefficients, using data from tapes made by Hewlett-Packard equipment employed for data acquisition on the spent Fuel Test - Climax at NTS. 12 references

Stock Picking via Nonsymmetrically Pruned Binary Decision Trees

OpenAIRE

Anton Andriyashin

2008-01-01

Stock picking is the field of financial analysis that is of particular interest for many professional investors and researchers. In this study stock picking is implemented via binary classification trees. Optimal tree size is believed to be the crucial factor in forecasting performance of the trees. While there exists a standard method of tree pruning, which is based on the cost-complexity tradeoff and used in the majority of studies employing binary decision trees, this paper introduces a no...

Order Picking Process in Warehouse: Case Study of Dairy Industry in Croatia

Directory of Open Access Journals (Sweden)

Josip Habazin

2017-02-01

Full Text Available The proper functioning of warehouse processes is fundamental for operational improvement and overall logistic supply chain improvement. Order picking is considered one of the most important from the group. Throughout picking orders in warehouses, the presence of human work is highly reflected, with the main goal to reduce the process time as much as possible, that is, to the very minimum. There are several different order picking methods, and nowadays, the most common ones are being developed and are significantly dependent on the type of goods, the warehouse equipment, etc., and those that stand out are scanning and picking by voice. This paper will provide information regarding the dairy industry in the Republic of Croatia with the analysis of order picking process in the observed company. Overall research highlighted the problem and resulted in proposals of solutions.

Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency

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Bret M. Evers

2017-09-01

Full Text Available Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL and Niemann-Pick type C (NPC, and is implicated in Alzheimer’s disease (AD and frontotemporal lobar degeneration (FTLD-TDP with progranulin (PGRN deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism.

Clinical and demographic features of vertigo: findings from the REVERT registry

Directory of Open Access Journals (Sweden)

Sam eAgus

2013-05-01

Full Text Available IntroductionDespite being a common disease, data on vertigo management in a real-world setting are scarce. AimsTo provide information on the vertigo and its management in a real-world setting.Materials and MethodsData were collected from 4,294 patients with vertigo in 13 countries over 28 months via a multi-national, non-interventional observational study (the so-called REVERT registry. Data included medical history and details of anti-vertigo therapy. ‘Clinical global impression’ (CGI of severity (CGI-S was assessed at baseline (V1 and then at 6 months follow-up (V2 along with CGI change (CGI-C. All variables were analysed descriptively. ResultsThe majority of patients were female, >40 years of age, and almost half had co-morbid cardiovascular disease. Diagnoses were split into 4 categories: 37.2% ‘other vertigo of peripheral vestibular origin’, 26.9% benign paroxysmal positional vertigo (BPPV, 20.5% ‘peripheral vestibular vertigo of unknown origin’ and 15.4% Menière’s disease (MD. Betahistine was the most commonly prescribed therapy prior to and after enrolment, and was followed by piracetam, ginkgo biloba and diuretics. MD had the highest proportion of betahistine treated patients. Almost half of patients were ‘moderately ill’ at V1 based on CGI-S. At V2, patient distribution moved towards ‘less severe illness’ (91.0% improved.The greatest improvements were in the more severely ill, and those with BPPV or ‘other vertigo of peripheral origin’. ConclusionsThere was a reduction in illness severity over the course of the study, some of which is likely to be due to pharmacological intervention. Further studies are needed to confirm these results.

Clinical and Demographic Features of Vertigo: Findings from the REVERT Registry

Science.gov (United States)

Agus, Sam; Benecke, Heike; Thum, Cornelia; Strupp, Michael

2013-01-01

Introduction: Despite being a common disease, data on vertigo management in a real-world setting are scarce. Aims: To provide information on the vertigo and its management in a real-world setting. Methods: Data were collected from 4,294 patients with vertigo in 13 countries over 28 months via a multi-national, non-interventional observational study (the so-called REVERT registry). Data included medical history and details of anti-vertigo therapy. “Clinical global impression” (CGI) of severity (CGI-S) was assessed at baseline (V1) and then at 6 months follow-up (V2) along with CGI change (CGI-C). All variables were analyzed descriptively. Results: The majority of patients were female, >40 years of age, and almost half had co-morbid cardio-vascular disease. Diagnoses were split into four categories: 37.2% “other vertigo of peripheral vestibular origin,” 26.9% benign paroxysmal positional vertigo (BPPV), 20.5% “peripheral vestibular vertigo of unknown origin,” and 15.4% Ménière’s disease (MD). Betahistine was the most commonly prescribed therapy prior to and after enrollment, and was followed by piracetam, ginkgo biloba, and diuretics. MD had the highest proportion of betahistine treated patients. Almost half of patients were “moderately ill” at V1 based on CGI-S. At V2, patient distribution moved toward “less severe illness” (91.0% improved). The greatest improvements were in the more severely ill, and those with BPPV or “other vertigo of peripheral origin.” Conclusion: There was a reduction in illness severity over the course of the study, some of which is likely to be due to pharmacological intervention. Further studies are needed to confirm these results. PMID:23675366

PAL-XFEL cavity beam position monitor pick-up design and beam test

Energy Technology Data Exchange (ETDEWEB)

Lee, Sojeong, E-mail: sojung8681@postech.ac.kr; Park, Young Jung; Kim, Changbum; Kim, Seung Hwan; Shin, Dong Cheol; Han, Jang-Hui; Ko, In Soo

2016-08-11

As an X-ray Free Electron Laser, PAL-XFEL is about to start beam commissioning. X-band cavity beam position monitor (BPM) is used in the PAL-XFEL undulator beam line. Prototypes of cavity BPM pick-up were designed and fabricated to test the RF characteristics. Also, the beam test of a cavity BPM pick-up was done in the Injector Test Facility (ITF). In the beam test, the raw signal properties of the cavity BPM pick-up were measured at a 200 pC bunch charge. According to the RF test and beam test results, the prototype cavity BPM pick-up design was confirmed to meet the requirements of the PAL-XFEL cavity BPM system.

Efficacy of the “pick and roll” offense in top level European basketball teams

Science.gov (United States)

Marmarinos, Christos; Kostopoulos, Nikolaos; Apostolidis, Alexandros

2016-01-01

Abstract Team offense in basketball games consists of a set of offensive actions carried out with the cooperation of two or more players. Of these actions, the most commonly used in the last decade is the on-ball screen called the “pick and roll.” The aim of this study was to analyze all of the pick and rolls conducted in the Euroleague championship from all of the 24 participating teams and to investigate the possible relationships between success in the pick and roll and overall success of the teams. For this purpose, 12,376 pick and rolls from 502 matches were analyzed and classified in categories according to the end result of the offensive possession. The results showed that the most effective type of pick and roll offense was when a shot was attempted after 2 passes from the pick and roll occurrence, followed by the screener’s shot when he rolled to the basket. Additionally, linear regression analysis confirmed that pick and roll effectiveness could predict the final classification of the teams. Conclusively, coaches of the high level European clubs should focus on training the players to the most efficient phases of the pick and roll offense, so that the chances of winning the championship to be maximized. PMID:28149375

Efficacy of the “pick and roll” offense in top level European basketball teams

Directory of Open Access Journals (Sweden)

Marmarinos Christos

2016-06-01

Full Text Available Team offense in basketball games consists of a set of offensive actions carried out with the cooperation of two or more players. Of these actions, the most commonly used in the last decade is the on-ball screen called the “pick and roll.” The aim of this study was to analyze all of the pick and rolls conducted in the Euroleague championship from all of the 24 participating teams and to investigate the possible relationships between success in the pick and roll and overall success of the teams. For this purpose, 12,376 pick and rolls from 502 matches were analyzed and classified in categories according to the end result of the offensive possession. The results showed that the most effective type of pick and roll offense was when a shot was attempted after 2 passes from the pick and roll occurrence, followed by the screener’s shot when he rolled to the basket. Additionally, linear regression analysis confirmed that pick and roll effectiveness could predict the final classification of the teams. Conclusively, coaches of the high level European clubs should focus on training the players to the most efficient phases of the pick and roll offense, so that the chances of winning the championship to be maximized.

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

NARCIS (Netherlands)

Kiritsi, Dimitra; He, Yinghong; Pasmooij, Anna M. G.; Onder, Meltem; Happle, Rudolf; Jonkman, Marcel F.; Bruckner-Tuderman, Leena; Has, Cristina

Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in

A Preliminary Analysis of the Phenomenology of Skin-Picking in Prader-Willi Syndrome

Science.gov (United States)

Morgan, Jessica R.; Storch, Eric A.; Woods, Douglas W.; Bodzin, Danielle; Lewin, Adam B.; Murphy, Tanya K.

2010-01-01

To examine the nature and psychosocial correlates of skin-picking behavior in youth with Prader-Willi Syndrome (PWS). Parents of 67 youth (aged 5-19 years) with PWS were recruited to complete an internet-based survey that included measures of: skin-picking behaviors, the automatic and/or focused nature of skin-picking, severity of skin-picking…

Skin Picking in Turkish Students: Prevalence, Characteristics, and Gender Differences

Science.gov (United States)

Calikusu, Celal; Kucukgoncu, Suat; Tecer, Ozlem; Bestepe, Emrem

2012-01-01

The aim of this study is to investigate the prevalence, characteristics, triggers, and consequences of skin picking (SP) in a sample of Turkish university students, with an emphasis on gender differences. A total of 245 students from two universities in Turkey were assessed by using the Skin Picking Inventory. In total, 87.8% of the students…

Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

Directory of Open Access Journals (Sweden)

Anja Meyer

2017-04-01

Full Text Available Niemann–Pick disease type C1 (NPC1 is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1−/− mutant mice compared with healthy controls (NPC1+/+. Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1−/− mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1−/− mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.

The number of pickers and stock-keeping unit arrangement on a uni-directional picking line

Directory of Open Access Journals (Sweden)

Hagspihl, Robert

2014-10-01

Full Text Available The order picking process is often the single largest expense in a distribution centre (DC. The DC considered in this paper uses a picking line configuration to perform order picking. The number of pickers in a picking line, and the initial arrangement of stock-keeping units (SKUs, are two important factors that affect the total completion time of the picking lines. In this paper, the picking line configuration is simulated with an agent-based approach to describe the behaviour of an individual picker. The simulation is then used to analyse the effect of the number of pickers and the SKU arrangement. Verification and validation of this model shows that the model represents the real-world picking line to a satisfactory degree. Marginal analysis (MA was chosen to determine a ‘good’ number of pickers by means of the simulation model. A look-up table is presented to provide decision support for the choice of a ‘good’ number of pickers to improve completion times of the picking line, for the properties of a specific picking line. The initial SKU arrangement on a picking line is shown to be a factor that can affect the level of picker congestion and the total completion time. The greedy ranking and partitioning (GRP and organ pipe arrangement (OPA techniques from the literature, as well as the historical SKU arrangements used by the retailer under consideration, were compared with the proposed classroom discipline heuristic (CDH for SKU arrangement. It was found that the CDH provides an more even spread of SKUs that are picked most frequently, thus decreasing congestion and total completion time.

Picking or nibbling: frequency and associated clinical features in bulimia nervosa, anorexia nervosa, and binge eating disorder.

Science.gov (United States)

Conceição, Eva M; Crosby, Ross; Mitchell, James E; Engel, Scott G; Wonderlich, Stephen A; Simonich, Heather K; Peterson, Caroline B; Crow, Scott J; Le Grange, Daniel

2013-12-01

Picking or ribbling (P&N) is a newly studied eating behavior characterized by eating in an unplanned and repetitious manner in between meals and snacks. This behavior seems to be related to poorer weight loss outcomes after bariatric surgery for weight loss in severely obese patients, but clarification is still required regarding its value in other clinical samples. The purpose of this study was to investigate the frequency of P&N across different eating disorder samples, as well as to examine its association with psychopathological eating disorder features. Our sample included treatment-seeking adult participants, recruited for five different clinical trials: 259 binge eating disorder (BED); 264 bulimia nervosa (BN), and 137 anorexia nervosa (AN). Participants were assessed using the Eating Disorders Examination interview before entering the clinical trials. P&N was reported by 44% of the BED; 57.6% of the BN; and 34.3% of the AN participants. No association was found between P&N and BMI, the presence of compensatory behaviors, binge eating, or any of the eating disorder examination subscales. This study suggests that P&N behavior is highly prevalent across eating disorder diagnoses, but it is not associated with psychopathology symptoms or other eating disordered behaviors. Copyright © 2013 Wiley Periodicals, Inc.

Clinic Attendance for Antiretroviral Pills Pick-Up among HIV-Positive People in Nepal: Roles of Perceived Family Support and Associated Factors.

Science.gov (United States)

Ayer, Rakesh; Kikuchi, Kimiyo; Ghimire, Mamata; Shibanuma, Akira; Pant, Madhab Raj; Poudel, Krishna C; Jimba, Masamine

2016-01-01

HIV-positive people's clinic attendance for medication pick-up is critical for successful HIV treatment. However, limited evidence exists on it especially in low-income settings such as Nepal. Moreover, the role of family support in clinic attendance remains under-explored. Therefore, this study was conducted to examine the association between perceived family support and regular clinic attendance and to assess factors associated with regular clinic attendance for antiretroviral pills pick-up among HIV-positive individuals in Nepal. A cross-sectional study was conducted among 423 HIV-positive people in three districts of Nepal. Clinic attendance was assessed retrospectively for the period of 12 months. To assess the factors associated, an interview survey was conducted using a semi-structured questionnaire from July to August, 2015. Multiple logistic regression models were used to assess the factors associated with regular clinic attendance. Of 423 HIV-positive people, only 32.6% attended the clinics regularly. They were more likely to attend them regularly when they received high family support (AOR = 3.98, 95% CI = 2.29, 6.92), participated in support programs (AOR = 1.68, 95% CI = 1.00, 2.82), and had knowledge on the benefits of antiretroviral therapy (AOR = 2.62, 95% CI = 1.15, 5.99). In contrast, they were less likely to attend them regularly when they commuted more than 60 minutes to the clinics (AOR = 0.53, 95% CI = 0.30, 0.93), when they self-rated their health status as being very good (AOR = 0.13, 95% CI = 0.04, 0.44), good (AOR = 0.14, 95% CI = 0.04, 0.46), and fair (AOR = 0.21, 95% CI = 0.06, 0.70). HIV-positive individuals are more likely to attend the clinics regularly when they receive high family support, know the benefits of antiretroviral therapy, and participate in support programs. To improve clinic attendance, family support should be incorporated with HIV care programs in resource limited settings. Service providers should also consider

Clinic Attendance for Antiretroviral Pills Pick-Up among HIV-Positive People in Nepal: Roles of Perceived Family Support and Associated Factors

Science.gov (United States)

Kikuchi, Kimiyo; Ghimire, Mamata; Shibanuma, Akira; Pant, Madhab Raj; Poudel, Krishna C.; Jimba, Masamine

2016-01-01

Introduction HIV-positive people’s clinic attendance for medication pick-up is critical for successful HIV treatment. However, limited evidence exists on it especially in low-income settings such as Nepal. Moreover, the role of family support in clinic attendance remains under-explored. Therefore, this study was conducted to examine the association between perceived family support and regular clinic attendance and to assess factors associated with regular clinic attendance for antiretroviral pills pick-up among HIV-positive individuals in Nepal. Methods A cross-sectional study was conducted among 423 HIV-positive people in three districts of Nepal. Clinic attendance was assessed retrospectively for the period of 12 months. To assess the factors associated, an interview survey was conducted using a semi-structured questionnaire from July to August, 2015. Multiple logistic regression models were used to assess the factors associated with regular clinic attendance. Results Of 423 HIV-positive people, only 32.6% attended the clinics regularly. They were more likely to attend them regularly when they received high family support (AOR = 3.98, 95% CI = 2.29, 6.92), participated in support programs (AOR = 1.68, 95% CI = 1.00, 2.82), and had knowledge on the benefits of antiretroviral therapy (AOR = 2.62, 95% CI = 1.15, 5.99). In contrast, they were less likely to attend them regularly when they commuted more than 60 minutes to the clinics (AOR = 0.53, 95% CI = 0.30, 0.93), when they self-rated their health status as being very good (AOR = 0.13, 95% CI = 0.04, 0.44), good (AOR = 0.14, 95% CI = 0.04, 0.46), and fair (AOR = 0.21, 95% CI = 0.06, 0.70). Conclusion HIV-positive individuals are more likely to attend the clinics regularly when they receive high family support, know the benefits of antiretroviral therapy, and participate in support programs. To improve clinic attendance, family support should be incorporated with HIV care programs in resource limited settings

Automatic first-break picking using the instantaneous traveltime attribute

KAUST Repository

Saragiotis, Christos

2012-01-01

Picking the first breaks is an important step in seismic processing. The large volume of the seismic data calls for automatic and objective picking. We introduce a new automatic first-break picker, which uses specifically designed time windows and an iterative procedure based on the instantaneous traveltime attribute. The method is fast as it only uses a few FFT\\'s per trace. We demonstrate the effectiveness of this automatic method by applying it on real test data.

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

Science.gov (United States)

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2013-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redistribution to clusters colocalizing with markers of recycling endosomal compartments. A similar clustering was observed both upon truncation of a short putative α-helical segment in the linker between the PDZ and the BAR domains and upon coexpression of PICK1 with a transmembrane PDZ ligand, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit, the GluR2 C-terminus transferred to the single transmembrane protein Tac or the dopamine transporter C-terminus transferred to Tac. In contrast, transfer of the GluR2 C-terminus to cyan fluorescent protein, a cytosolic protein, did not elicit BAR domain-dependent clustering. Instead, localizing PICK1 to the membrane by introducing an N-terminal myristoylation site produced BAR domain-dependent, but ligand-independent, PICK1 clustering. The data support that in the absence of PDZ ligand, the PICK1 BAR domain is inhibited through a PDZ domain-dependent and linker-dependent mechanism. Moreover, they suggest that unmasking of the BAR domain’s membrane-binding capacity is not a consequence of ligand binding to the PDZ domain per se but results from, and coincides with, recruitment of PICK1 to a membrane compartment. PMID:18466293

How 'ground-picked' olive fruits affect virgin olive oil ethanol content, ethyl esters and quality.

Science.gov (United States)

Beltran, Gabriel; Sánchez, Raquel; Sánchez-Ortiz, Araceli; Aguilera, Maria P; Bejaoui, Mohamed A; Jimenez, Antonio

2016-08-01

Olives dropped on the ground naturally sometimes are not separated from those fresh and healthy collected from the tree for harvest and processing. In this work we compared the quality, ethanol content and bioactive components of virgin olive oils from ground-picked olives, tree-picked fruits and their mixture. Ground-picked olives produced 'Lampante' virgin olive oils; these are of a lower quality category, because of important alterations in chemical and sensory characteristics. Ethyl esters showed the highest values, although under the regulated limit. The mixture of ground and tree-picked olives gave oils classified as 'virgin' because of sensory defects, although the quality parameters did not exceed the limits for the 'extra' category. Ethanol content showed a significant increase in the oils from ground- picked olives and their mixture with respect to those from tree-picked fruits. Furthermore, bioactive compounds showed a significant decrease as fruit quality was poorer. Ground-picked olives must be harvested and processed separately since they produce low-quality virgin olive oils with sensory defects and lower concentrations of bioactive compounds. The higher acidity and ethanol concentration observed in oils from ground-picked fruits or their mixture may help ethyl ester synthesis during storage. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

The correlation between cherry picking and the distance that consumers travel to do grocery shopping

Directory of Open Access Journals (Sweden)

Louise Van Scheers

2013-04-01

Full Text Available Retailers often use price promotions to discriminate between consumers who can shift purchases over time and those who cannot. Retailers consistently tend to charge lower prices than necessary, pricing defensively to prevent loyal customers from cherry picking, or shifting to competitors. Knowledge about cherry picking behaviour will enable retailers to obtain a higher share of disposable income from even price-sensitive shoppers, while at the same time charging higher prices. Recent studies indicate that effective cherry picking entails saving costs through price searching over time, price searching across stores, or both. This study examines the relationship between cherry picking and the distance that consumers travel to do grocery shopping. Interviews were conducted at ten different retail outlets over three days, and the results show that there is a highly significant correlation between cherry picking and the distance that consumers travel to do grocery shopping.These results should help retailers to benefit from cherry picking by taking a proactive approach to store switching and store location, two of the main influences on cherry picking behaviour.

The class characteristic mark of the H&M Mul-T-Lock picking tool in toolmarks examination.

Science.gov (United States)

Volkov, Nikolai; Finkelstein, Nir; Novoselsky, Yehuda; Tsach, Tsadok

2014-07-01

Mul-T-Lock is a high security lock cylinder distinguished by the use of a telescoping "pin-in-pin"-tumbler design. Picking the Mul-T-Lock cylinder with a traditional picking tool is highly complicated because it can get stuck between the inner and outer pins. The H&M Mul-T-Lock picking tool was designed to overcome this problem and facilitate the picking of the "pin-in-pin" cylinder. The purpose of this research is to determine whether H&M Mul-T-Lock picking tool leaves class characteristic mark and whether it can be distinguished from traditional picking tools marks and from regular key marks. It also describes and determines the class characteristic mark left on telescopic pins, its origin, recurrence, and its benefit to the toolmarks examiner. When receiving a Mul-T-Lock from a crime scene, a toolmarks examiner can quickly determine whether or not it was picked by an H&M Mul-T-Lock picking tool by noticing the class characteristic mark which this typical tool leaves. © 2014 American Academy of Forensic Sciences.

Automated Peak Picking and Peak Integration in Macromolecular NMR Spectra Using AUTOPSY

Science.gov (United States)

Koradi, Reto; Billeter, Martin; Engeli, Max; Güntert, Peter; Wüthrich, Kurt

1998-12-01

A new approach for automated peak picking of multidimensional protein NMR spectra with strong overlap is introduced, which makes use of the program AUTOPSY (automatedpeak picking for NMRspectroscopy). The main elements of this program are a novel function for local noise level calculation, the use of symmetry considerations, and the use of lineshapes extracted from well-separated peaks for resolving groups of strongly overlapping peaks. The algorithm generates peak lists with precise chemical shift and integral intensities, and a reliability measure for the recognition of each peak. The results of automated peak picking of NOESY spectra with AUTOPSY were tested in combination with the combined automated NOESY cross peak assignment and structure calculation routine NOAH implemented in the program DYANA. The quality of the resulting structures was found to be comparable with those from corresponding data obtained with manual peak picking.

CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein (MTP)

DEFF Research Database (Denmark)

Rakhshandehroo, Maryam; Gijzel, Sanne M W; Siersbæk, Rasmus

2014-01-01

-dependent fashion, but little is known about the lipid antigen presentation machinery in adipocytes. Here we show that CD1d, as well as the lipid antigen loading machinery genes pro-saposin (Psap), Niemann Pick type C2 (Npc2), α-galactosidase (Gla), are upregulated in early adipogenesis, and are transcriptionally...... presenting cells (APCs), which may present an important aspect of adipocyte-immune cell communication in the regulation of whole body energy metabolism and immune homeostasis....

Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.

Directory of Open Access Journals (Sweden)

Qingyu Qin

Full Text Available Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK and murine double minute (Mdm2 E3 ligase. Growth cone collapse induced by genetic (npc1-/- or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.

Cholesterol: Its Regulation and Role in Central Nervous System Disorders

Directory of Open Access Journals (Sweden)

Matthias Orth

2012-01-01

Full Text Available Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules. We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

21 CFR 872.6650 - Massaging pick or tip for oral hygiene.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Massaging pick or tip for oral hygiene. 872.6650 Section 872.6650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... hygiene. (a) Identification. A massaging pick or tip for oral hygiene is a rigid, pointed device intended...

Automatic Grasp Generation and Improvement for Industrial Bin-Picking

DEFF Research Database (Denmark)

Kraft, Dirk; Ellekilde, Lars-Peter; Rytz, Jimmy Alison

2014-01-01

and achieve comparable results and that our learning approach can improve system performance significantly. Automatic bin-picking is an important industrial process that can lead to significant savings and potentially keep production in countries with high labour cost rather than outsourcing it. The presented......This paper presents work on automatic grasp generation and grasp learning for reducing the manual setup time and increase grasp success rates within bin-picking applications. We propose an approach that is able to generate good grasps automatically using a dynamic grasp simulator, a newly developed...

Grasp Densities for Grasp Refinement in Industrial Bin Picking

DEFF Research Database (Denmark)

Hupfauf, Benedikt; Hahn, Heiko; Bodenhagen, Leon

in terms of object-relative gripper pose, can be learned from empirical experience, and allow the automatic choice of optimal grasps in a given scene context (object pose, workspace constraints, etc.). We will show grasp densities extracted from empirical data in a real industrial bin picking context...... generated in industrial bin-picking for grasp learning. This aim is achieved by using the novel concept of grasp densities (Detry et al., 2010). Grasp densities can describe the full variety of grasps that apply to specific objects using specific grippers. They represent the likelihood of grasp success...

Soyamilk fermented with riboflavin-producing Lactobacillus plantarum CRL 2130 reverts and prevents ariboflavinosis in murine models.

Science.gov (United States)

Juarez Del Valle, M; Laiño, J E; de Moreno de LeBlanc, A; Savoy de Giori, G; LeBlanc, J G

2016-10-01

It has been previously shown that Lactobacillus plantarum CRL 2130 is able to produce riboflavin in soyamilk. The aim of the present study was to evaluate the efficiency of this riboflavin-bio-enriched soyamilk to revert and/or prevent the nutritional deficiency of riboflavin using different animal models. When used to supplement the diets of previously depleted animals, it was shown that the growth, riboflavin status and morphology of the small intestines reverted to normal parameters and were similar to animals supplemented with commercial riboflavin. In the prevention model, the same tendency was observed, where animals that received soyamilk fermented with L. plantarum CRL 2130 did not show signs of riboflavin deficiency. This new bio-fortified soya-based product could be used as part of normal diets to provide a more natural alternative to mandatory fortification with riboflavin for the prevention of its deficiency.

Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts

DEFF Research Database (Denmark)

Berzina, Zane; Solanko, Lukasz M; Mehadi, Ahmed S

2018-01-01

/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous...... but not of DHE is reduced 10-fold in disease fibroblasts compared to control cells. Internalized NPC2 rescued the sterol storage phenotype and strongly expanded the dynamic sterol pool seen in FRAP experiments. Together, our study shows that cholesterol esterification and trafficking of sterols between the PM...

Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content.

Directory of Open Access Journals (Sweden)

Hanna Appelqvist

Full Text Available Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1 protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2, which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determineD the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

Pick-Up Ion Instabilities at Planetary Magnetospheres

Science.gov (United States)

Strangeway, Robert J.; Sharber, James (Technical Monitor)

2001-01-01

wave modes can be drive unstable by the pressure anisotropy associated with the pick up ions. The pick ion velocity is perpendicular to the ambient magnetic field, and is generally much larger than the thermal velocity, at least initially. At its simplest, we found that the ion cyclotron waves are controlled by the parameters of the species in gyro-resonance with the wave. Thus, while the growth rates for the lower mass (higher gyro-frequency) pick-up ions are generally larger, we found that the heavier SO2+ ion cyclotron waves are generally preferred. This is because one of the effects of the wave instability is to diffuse the ions in pitch angle and energy. The lower mass ions therefore consist of both a ring of recently created pick-up ions, and a thermal background. This thermal background quenches the ion cyclotron instability. SO2+ is different, however. Being a molecule, the species can also dissociate. Our analysis suggests that the dissociation acts on a time scale comparable to or faster than the velocity space diffusion time scale. There are consequently no thermal SO2+ ions to quench the instability. We have also investigated the mirror-mode. This mode can at times grow more rapidly than the individual ion cyclotron waves. This is mainly because the mirror-mode can grow off the pressure anisotropy of the individual species with which the waves are in resonance. Lastly, as part of this effort we have begun to investigate the instability for obliquely propagating modes. Galileo observations show that at times the ion cyclotron waves are significantly elliptically polarized, and further the wave vector is at a large angle to the field, significant growth can occur for oblique propagation. Depending on the group velocity of the waves, it is possible that obliquely propagating modes have higher advective growth rate, but this has yet to be determined.

Evaluation of strip-line pick-up system for the SPS wideband transverse feedback system

CERN Document Server

Kotzian, G; Steinhagen, R J; Valuch, D; Wehrle, U

2017-01-01

The proposed SPS Wideband Transverse Feedback sys- tem requires a wide-band pick-up system to be able to de- tect intra-bunch motion within the SPS proton bunches, captured and accelerated in a 200 MHz bucket. We present the electro-magnetic design of transverse beam position pick-up options optimised for installation in the SPS and evaluate their performance reach with respect to direct time domain sampling of the intra-bunch motion. The analy- sis also discusses the achieved subsystem responses of the associated cabling with new low dispersion smooth wall coaxial cables, wide-band generation of intensity and posi- tion signals by means of 180 degree RF hybrids as well as passive techniques to electronically suppress the beam off- set signal, needed to optimise the dynamic range and posi- tion resolution of the planned digital intra-bunch feedback system.

Concerted regulation of npc2 binding to endosomal/lysosomal membranes by bis(monoacylglycero)phosphate and sphingomyelin

DEFF Research Database (Denmark)

Enkavi, Giray; Mikkolainen, Heikki; Güngör, Burçin

2017-01-01

remained elusive. Here, based on an extensive set of atomistic simulations and free energy calculations, we clarify the mechanism and energetics of npc2-membrane binding and characterize the roles of physiologically relevant key lipids associated with the binding process. Our results capture in atomistic......Niemann-Pick Protein C2 (npc2) is a small soluble protein critical for cholesterol transport within and from the lysosome and the late endosome. Intriguingly, npc2-mediated cholesterol transport has been shown to be modulated by lipids, yet the molecular mechanism of npc2-membrane interactions has......). This mode is associated with cholesterol uptake and release. On the other hand, the second mode (Supine) places the cholesterol binding pocket away from the membrane surface, but has overall higher membrane binding affinity. We determined that bis(monoacylglycero)phosphate (bmp) is specifically required...

Nibbling and picking in obese patients with Binge Eating Disorder.

Science.gov (United States)

Masheb, Robin M; Roberto, Christina A; White, Marney A

2013-12-01

The goal of this study was to examine the clinical utility of nibbling behavior, defined as eating in an unplanned and repetitious manner between meals and snacks without a sense of loss of control, in obese patients with Binge Eating Disorder (BED). Two-hundred seventeen (N = 217) consecutive, treatment-seeking, obese patients with BED were assessed with the Eating Disorder Examination (EDE). Nibbling frequency was examined in relation to current weight, eating disorder psychopathology and eating patterns. Results found that nibbling/picking was not related to body mass index, objective bulimic, subjective bulimic, or overeating episodes, food avoidance, sensitivity to weight gain, or any subscales of the EDE. However, nibbling/picking was significantly related to frequency of morning and afternoon snacking (r = .21, p = .002; r = .27, p < .001). The assessment of nibbling/picking behaviors among individuals with BED might not provide clinically significant information. © 2013.

Belt for picking up liquids

Energy Technology Data Exchange (ETDEWEB)

Sewell, R B.H.; Nelson, S P

1973-05-18

This belt for picking up liquids consists of a layer of strong material, e.g., coarse cloth, sewed on at least one layer of absorbing material, e.g., sponge cloth, the stitching being disposed along chevrons with their apexes along the central axis of the belt; the edges do not contain any other marks. This arrangement facilitates the expulsion of the absorbed liquid when the belt passes between compression rollers.

Arrival-time picking method based on approximate negentropy for microseismic data

Science.gov (United States)

Li, Yue; Ni, Zhuo; Tian, Yanan

2018-05-01

Accurate and dependable picking of the first arrival time for microseismic data is an important part in microseismic monitoring, which directly affects analysis results of post-processing. This paper presents a new method based on approximate negentropy (AN) theory for microseismic arrival time picking in condition of much lower signal-to-noise ratio (SNR). According to the differences in information characteristics between microseismic data and random noise, an appropriate approximation of negentropy function is selected to minimize the effect of SNR. At the same time, a weighted function of the differences between maximum and minimum value of AN spectrum curve is designed to obtain a proper threshold function. In this way, the region of signal and noise is distinguished to pick the first arrival time accurately. To demonstrate the effectiveness of AN method, we make many experiments on a series of synthetic data with different SNR from -1 dB to -12 dB and compare it with previously published Akaike information criterion (AIC) and short/long time average ratio (STA/LTA) methods. Experimental results indicate that these three methods can achieve well picking effect when SNR is from -1 dB to -8 dB. However, when SNR is as low as -8 dB to -12 dB, the proposed AN method yields more accurate and stable picking result than AIC and STA/LTA methods. Furthermore, the application results of real three-component microseismic data also show that the new method is superior to the other two methods in accuracy and stability.

Collision free pick up and movement of large objects

International Nuclear Information System (INIS)

Drotning, W.D.; McKee, G.R.

1998-01-01

An automated system is described for the sensor-based precision docking and manipulation of large objects. Past work in the remote handling of large nuclear waste containers is extensible to the problems associated with the handling of large objects such as coils of flat steel in industry. Computer vision and ultrasonic proximity sensing as described here are used to control the precision docking of large objects, and swing damped motion control of overhead cranes is used to control the position of the pick up device and suspended payload during movement. Real-time sensor processing and model-based control are used to accurately position payloads

Podocyte Pathology and Nephropathy

Directory of Open Access Journals (Sweden)

Sandra eMerscher

2014-07-01

Full Text Available Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay-Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann-Pick and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarily, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD, HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b is expressed in podocytes where it modulates acid sphingomyelinase (ASMase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

Robotic vision system for random bin picking with dual-arm robots

Directory of Open Access Journals (Sweden)

Kang Sangseung

2016-01-01

Full Text Available Random bin picking is one of the most challenging industrial robotics applications available. It constitutes a complicated interaction between the vision system, robot, and control system. For a packaging operation requiring a pick-and-place task, the robot system utilized should be able to perform certain functions for recognizing the applicable target object from randomized objects in a bin. In this paper, we introduce a robotic vision system for bin picking using industrial dual-arm robots. The proposed system recognizes the best object from randomized target candidates based on stereo vision, and estimates the position and orientation of the object. It then sends the result to the robot control system. The system was developed for use in the packaging process of cell phone accessories using dual-arm robots.

The burden and impact of vertigo: findings from the REVERT patient registry

Directory of Open Access Journals (Sweden)

Heike eBenecke

2013-10-01

Full Text Available Objective: Despite the high prevalence of vertigo globally and an acknowledged, but underreported, effect on an individual’s wellbeing, few studies have evaluated the burden on healthcare systems and society. This study was aimed to quantitatively determine the impact of vertigo on healthcare resource use and work productivity. Methods: The economic burden of vertigo was assessed through a multi-country, non-interventional, observational registry of vertigo patients: the Registry to Evaluate the Burden of Disease in Vertigo (REVERT. Patients included were those with a new diagnosis of Meniere’s disease (MD, benign paroxysmal positional vertigo (BPPV, other vertigo of peripheral vestibular origin or peripheral vestibular vertigo of unknown origin. Results: A total of 4,294 patients at 618 centers in 13 countries were included during the registry. Of the 4,105 patients analyzed, only half were in employment. Among this working patient population, 69.8% had reduced their workload, 63.3% had lost working days and 4.6% had changed and 5.7% had quit their jobs, due to vertigo symptoms. Use of healthcare services among patients was high. In the 3 months preceding Visit 1, patients used emergency services 0.4 ± 0.9 times, primary care consultations 1.6 ± 1.8 times and specialist consultations 1.4 ± 2.0 times (all mean ± SD. A mean of 2.0 ± 5.4 days/patient was also spent in hospital due to vertigo.Conclusions: In addition to the negative impact on the patient from a humanistic perspective, vertigo has considerable impact on work productivity and healthcare resource use.

A theoretical model for predicting the Peak Cutting Force of conical picks

Directory of Open Access Journals (Sweden)

Gao Kuidong

2014-01-01

Full Text Available In order to predict the PCF (Peak Cutting Force of conical pick in rock cutting process, a theoretical model is established based on elastic fracture mechanics theory. The vertical fracture model of rock cutting fragment is also established based on the maximum tensile criterion. The relation between vertical fracture angle and associated parameters (cutting parameter  and ratio B of rock compressive strength to tensile strength is obtained by numerical analysis method and polynomial regression method, and the correctness of rock vertical fracture model is verified through experiments. Linear regression coefficient between the PCF of prediction and experiments is 0.81, and significance level less than 0.05 shows that the model for predicting the PCF is correct and reliable. A comparative analysis between the PCF obtained from this model and Evans model reveals that the result of this prediction model is more reliable and accurate. The results of this work could provide some guidance for studying the rock cutting theory of conical pick and designing the cutting mechanism.

Stochastic price modeling of high volatility, mean-reverting, spike-prone commodities: The Australian wholesale spot electricity market

International Nuclear Information System (INIS)

Higgs, Helen; Worthington, Andrew

2008-01-01

It is commonly known that wholesale spot electricity markets exhibit high price volatility, strong mean-reversion and frequent extreme price spikes. This paper employs a basic stochastic model, a mean-reverting model and a regime-switching model to capture these features in the Australian national electricity market (NEM), comprising the interconnected markets of New South Wales, Queensland, South Australia and Victoria. Daily spot prices from 1 January 1999 to 31 December 2004 are employed. The results show that the regime-switching model outperforms the basic stochastic and mean-reverting models. Electricity prices are also found to exhibit stronger mean-reversion after a price spike than in the normal period, and price volatility is more than fourteen times higher in spike periods than in normal periods. The probability of a spike on any given day ranges between 5.16% in NSW and 9.44% in Victoria

Development of a doorframe-typed swinging seedling pick-up device for automatic field transplantation

Energy Technology Data Exchange (ETDEWEB)

Han, H.; Mao, H.; Hu, J.; Tian, K.

2015-07-01

A doorframe-typed swing seedling pick-up device for automatic field transplanters was developed and evaluated in a laboratory. The device, consisting of a path manipulator and two grippers, can move the pins slowly to extract seedlings from the tray cells and return quickly to the pick-up point for the next extraction. The path manipulator was constructed with the creative design of type-Ⅱ mechanism combination in series. It consists of an oscillating guide linkage mechanism and a grooved globoidal cam mechanism. The gripper is a pincette-type mechanism using the pick-up pins to penetrate into the root mass for seedling extraction. The dynamic analysis of the designed seedling pick-up device was simulated with ADAMS software. Being the first prototype, various performance tests under local production conditions were conducted to find out the optimal machine operation parameters and transplant production conditions. As the gripper with multiple fine pins was moved by the swing pick-up device, it can effectively complete the transplanting work cycle of extracting, transferring, and discharging a seedling. The laboratory evaluation showed that the pick-up device equipped with two grippers can extract 80 seedlings/min with a 90% success and a 3% failure in discharging seedlings, using 42-day-old tomato plantlets. The quality of extracting seedlings was satisfactory. (Author)

Solenoid pick-up problem in the CREN-K Triga Mark 2 reactor

International Nuclear Information System (INIS)

Malu wa Kalenga; Kobakozete Itono; Diazengwa Mpaka; Mampaka Mana Mouiny; Itio Momba

1981-01-01

During a lazy susan forty irradiation tube inspection with the specimen lifting device, the solenoid-operated specimen pick-up tool happened to be locked in the number fourteen position loading tube. The present paper describes the successful experiment which was carried out to solve a potential damaging situation for the safe and useful operation of the reactor. The first step in the investigation process was to ascertain what has indeed occurred in the reactor core to avoid any ill advised step which will worsen the situation. The alternatives were the following: a) The specimen tube was not lined with the loading tube; b) The lazy susan was not working properly due example to the fact that a roll pin in a drive shaft coupling inside the drive shaft tube has been broken; c) The pick-up tool has produced through the cleanout hole in the bottom of the specimen tube and engage the hole; d) The pick-up tool might have slided most of the way between the lazy susan and its housing. By moving up and down the pick-up tool and rotating back and forth the lazy susan it was possible to come to the conclusion that alternative c) was the most likely. It was not possible to release the pick-up tool because its engaging arms could not be activated as was often the case when lifting aluminium container

Solenoid pick-up problem in the CREN-K Triga Mark 2 reactor

Energy Technology Data Exchange (ETDEWEB)

Malu wa Kalenga; Kobakozete Itono; Diazengwa Mpaka; Mampaka Mana Mouiny; Itio Momba (Commissariat des Sciences Nucleaires, Kinshasa (Zaire). Centre Regional d' Etudes Nucleaires)

1981-01-01

During a lazy susan forty irradiation tube inspection with the specimen lifting device, the solenoid-operated specimen pick-up tool happened to be locked in the number fourteen position loading tube. The present paper describes the successful experiment which was carried out to solve a potential damaging situation for the safe and useful operation of the reactor. The first step in the investigation process was to ascertain what has indeed occurred in the reactor core to avoid any ill advised step which will worsen the situation. The alternatives were the following: a) The specimen tube was not lined with the loading tube; b) The lazy susan was not working properly due example to the fact that a roll pin in a drive shaft coupling inside the drive shaft tube has been broken; c) The pick-up tool has produced through the cleanout hole in the bottom of the specimen tube and engage the hole; d) The pick-up tool might have slided most of the way between the lazy susan and its housing. By moving up and down the pick-up tool and rotating back and forth the lazy susan it was possible to come to the conclusion that alternative c) was the most likely. It was not possible to release the pick-up tool because its engaging arms could not be activated as was often the case when lifting aluminium container.

Cellular Signaling in Health and Disease

CERN Document Server

Beckerman, Martin

2009-01-01

In today’s world, three great classes of non-infectious diseases – the metabolic syndromes (such as type 2 diabetes and atherosclerosis), the cancers, and the neurodegenerative disorders – have risen to the fore. These diseases, all associated with increasing age of an individual, have proven to be remarkably complex and difficult to treat. This is because, in large measure, when the cellular signaling pathways responsible for maintaining homeostasis and health of the body become dysregulated, they generate equally stable disease states. As a result the body may respond positively to a drug, but only for a while and then revert back to the disease state. Cellular Signaling in Health and Disease summarizes our current understanding of these regulatory networks in the healthy and diseased states, showing which molecular components might be prime targets for drug interventions. This is accomplished by presenting models that explain in mechanistic, molecular detail how a particular part of the cellular sign...

Habit Reversal as a Treatment for Chronic Skin Picking: A Pilot Investigation

Science.gov (United States)

Teng, Ellen J.; Woods, Douglas W.; Twohig, Michael P.

2006-01-01

The purpose of this study was to compare the effectiveness of habit reversal (HR) to a wait-list control as a treatment for chronic skin picking in adults. Twenty-five adults with a chronic skin-picking problem were randomly assigned to a wait-list control or HR group. At pretreatment, posttreatment, and a 3-month follow-up, self-reported skin…

Make their bets

International Nuclear Information System (INIS)

Bravo, Oscar

2004-01-01

The paper refers to the growing demand of petroleum and until when will be able to satisfy, because most of the nations producers of petroleum have arrived to the pick of the extraction and they have not been able to revert this situation

Derivados de aminociclitoles, procedimiento de obtención y usos

OpenAIRE

Díaz Bueno, Lucía; Casas Brugulat, Josefina; Bujons Vilàs, Jordi; Egido Gabás, Meritxell; Delgado Cirilo, Antonio; Llebaria, Amadeu

2009-01-01

La presente invención se refiere a los compuestos de fórmula general (1) ya sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de TaySachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann-Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obte...

A multi-objective approach to the assignment of stock keeping units to unidirectional picking lines

Directory of Open Access Journals (Sweden)

Le Roux, G. J.

2017-05-01

Full Text Available An order picking system in a distribution centre consisting of parallel unidirectional picking lines is considered. The objectives are to minimise the walking distance of the pickers, the largest volume of stock on a picking line over all picking lines, the number of small packages, and the total penalty incurred for late distributions. The problem is formulated as a multi-objective multiple knapsack problem that is not solvable in a realistic time. Population-based algorithms, including the artificial bee colony algorithm and the genetic algorithm, are also implemented. The results obtained from all algorithms indicate a substantial improvement on all objectives relative to historical assignments. The genetic algorithm delivers the best performance.

75 FR 22423 - Pick-Sloan Missouri Basin Program, Eastern and Western Division Proposed Project Use Power Rate

Science.gov (United States)

2010-04-28

...: Reopening of comment period for review of the Pick-Sloan Missouri Basin Program, Eastern and Western... reopening the comment period for the Pick-Sloan Missouri Basin Program, Eastern and Western Division... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Pick-Sloan Missouri Basin Program, Eastern and...

75 FR 1408 - Pick-Sloan Missouri Basin Program, Eastern and Western Division Proposed Project Use Power Rate

Science.gov (United States)

2010-01-11

... of Proposed Pick-Sloan Missouri Basin Program, Eastern and Western Divisions, Project Use Power Rate...) for Project Use Power for the Pick-Sloan Missouri Basin Program (P-SMBP), Eastern and Western... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Pick-Sloan Missouri Basin Program, Eastern and...

Climate Change and Fruit-Picking Tourism: Impact and Adaptation

Directory of Open Access Journals (Sweden)

Jun Liu

2016-01-01

Full Text Available The purpose of this work is to present phenology as a valid indicator and methodology for monitoring and assessing the impact of climate change on plant-based tourist activities. Fruit-picking has become a popular rural tourism activity worldwide. However, fruit maturity dates (FMD have been affected by climate change (CC, which has in turn profoundly affected fruit-picking tourism activities (FPTA. In this paper, phenological data on the FMD for 45 types of plants in 1980–2012, dates for more than 200 fruit-picking festivals, and data on monthly average air temperature in 1980–2013 were used to assess the impact of CC on FPTA by wavelet and correlation analyses. The findings indicated that the study area had been significantly affected by CC. Prevailing temperatures at one or three months prior have a decisive influence on FMD. Among the 11 plants directly related to FPTA, the FMD of four were significantly advanced, while 6-7 were significantly delayed owning to increased temperature. Of the 11 FPTA, only two had realized the impact of CC and had adjusted festival opening dates based on dynamic changes. However, a considerable number of festival activities remained fixed or scheduled on the weekends.

Warehouse order-picking process. Order-picker routing problem

Directory of Open Access Journals (Sweden)

E. V. Korobkov

2015-01-01

Full Text Available This article continues “Warehouse order-picking process” cycle and describes order-picker routing sub-problem of a warehouse order-picking process. It draws analogies between the orderpickers’ routing problem and traveling salesman’s problem, shows differences between the standard problem statement of a traveling salesman and routing problem of warehouse orderpickers, and gives the particular Steiner’s problem statement of a traveling salesman.Warehouse layout with a typical order is represented by a graph, with some its vertices corresponding to mandatory order-picker’s visits and some other ones being noncompulsory. The paper describes an optimal Ratliff-Rosenthal algorithm to solve order-picker’s routing problem for the single-block warehouses, i.e. warehouses with only two crossing aisles, defines seven equivalent classes of partial routing sub-graphs and five transitions used to have an optimal routing sub-graph of a order-picker. An extension of optimal Ratliff-Rosenthal order-picker routing algorithm for multi-block warehouses is presented and also reasons for using the routing heuristics instead of exact optimal algorithms are given. The paper offers algorithmic description of the following seven routing heuristics: S-shaped, return, midpoint, largest gap, aisle-by-aisle, composite, and combined as well as modification of combined heuristics. The comparison of orderpicker routing heuristics for one- and two-block warehouses is to be described in the next article of the “Warehouse order-picking process” cycle.

Detection of interstellar pick-up hydrogen in the solar system

Science.gov (United States)

Gloeckler, G.; Geiss, J.; Balsiger, H.; Fisk, L. A.; Galvin, A. B.; Ipavich, F. M.; Ogilvie, K. W.; Von Steiger, R.; Wilken, B.

1993-01-01

Interstellar hydrogen ionized primarily by the solar wind has been detected by the Solar Wind Ion Composition Spectrometer instrument on the Ulysses spacecraft at a distance of 4.8 AUs from the sun. This 'pick-up' hydrogen is identified by its distinct velocity distribution function, which drops abruptly at twice the local solar wind speed. From the measured fluxes of pick-up protons and singly charged helium, the number densities of neutral hydrogen and helium in the distant regions of the solar system are estimated to be 0.077 +/- 0.015 and 0.013 +/- 0.003 per cu cm, respectively.

Benchmarking motion planning algorithms for bin-picking applications

DEFF Research Database (Denmark)

Iversen, Thomas Fridolin; Ellekilde, Lars-Peter

2017-01-01

Purpose For robot motion planning there exists a large number of different algorithms, each appropriate for a certain domain, and the right choice of planner depends on the specific use case. The purpose of this paper is to consider the application of bin picking and benchmark a set of motion...... planning algorithms to identify which are most suited in the given context. Design/methodology/approach The paper presents a selection of motion planning algorithms and defines benchmarks based on three different bin-picking scenarios. The evaluation is done based on a fixed set of tasks, which are planned...... and executed on a real and a simulated robot. Findings The benchmarking shows a clear difference between the planners and generally indicates that algorithms integrating optimization, despite longer planning time, perform better due to a faster execution. Originality/value The originality of this work lies...

Fifteen Minutes of Fame? The Market Impact of Internet Stock Picks

OpenAIRE

Peter Antunovich; Asani Sarkar

2006-01-01

We examine 120 Nasdaq and Over-the-Counter "buy" recommendations made by Internet sites from April 1999 to June 2001. The stock picks show substantial short- and long-run price and liquidity gains, although no new information is revealed about them. For example, liquidity one year after the pick day remains higher for these stocks than for a sample matched according to size, book-to-market value, and liquidity in the preceding year. In addition, after controlling for fundamental and microstru...

Single neutron pick-up on 104Pd

International Nuclear Information System (INIS)

Rodrigues, M.R.D.; Andre, J.P.A.M. de; Borello-Lewin, T.; Horodynski-Matsushigue, L.B.; Duarte, J.L.M.; Rodrigues, C.L.; Ukita, G.M.

2006-01-01

Low-lying levels of 103 Pd have been investigated through the (d,t) reaction on 104 Pd, at an incident deuteron energy of 15.0 MeV. Outgoing particles were momentum analyzed by an Enge magnetic spectrograph and detected in nuclear emulsion plates, with an energy resolution of 8 keV. Previous (d,t) work suffered from a much worse resolution than that here achieved. A partial analysis of the data obtained is reported, referring to six out of the fourteen scattering angles for which data were obtained. Angular distributions associated with eight of the thirteen levels seen up to 1.1 MeV of excitation have been compared to DWBA one-neutron pick-up predictions. Both, the attributed excitation energy values and the transferred angular momenta are in excellent agreement with the results of other kind of experiments, as tabulated by the Nuclear Data Sheets. Some peculiar structure characteristics, associated with the yrast 5/2 + , 3/2 + and 7/2 + states found in the Ru chain could be recognized also in 103 Pd, pointing to the possibility of a more global understanding of this transitional mass region. (author)

A Semiautomated Multilayer Picking Algorithm for Ice-sheet Radar Echograms Applied to Ground-Based Near-Surface Data

Science.gov (United States)

Onana, Vincent De Paul; Koenig, Lora Suzanne; Ruth, Julia; Studinger, Michael; Harbeck, Jeremy P.

2014-01-01

Snow accumulation over an ice sheet is the sole mass input, making it a primary measurement for understanding the past, present, and future mass balance. Near-surface frequency-modulated continuous-wave (FMCW) radars image isochronous firn layers recording accumulation histories. The Semiautomated Multilayer Picking Algorithm (SAMPA) was designed and developed to trace annual accumulation layers in polar firn from both airborne and ground-based radars. The SAMPA algorithm is based on the Radon transform (RT) computed by blocks and angular orientations over a radar echogram. For each echogram's block, the RT maps firn segmented-layer features into peaks, which are picked using amplitude and width threshold parameters of peaks. A backward RT is then computed for each corresponding block, mapping the peaks back into picked segmented-layers. The segmented layers are then connected and smoothed to achieve a final layer pick across the echogram. Once input parameters are trained, SAMPA operates autonomously and can process hundreds of kilometers of radar data picking more than 40 layers. SAMPA final pick results and layer numbering still require a cursory manual adjustment to correct noncontinuous picks, which are likely not annual, and to correct for inconsistency in layer numbering. Despite the manual effort to train and check SAMPA results, it is an efficient tool for picking multiple accumulation layers in polar firn, reducing time over manual digitizing efforts. The trackability of good detected layers is greater than 90%.

Necessity and complexity of order picking routing optimisation based on pallet loading features

Directory of Open Access Journals (Sweden)

Bódis Tamás

2017-12-01

Full Text Available Order picking is the most labour-intensive and costly activity of warehouses. The main challenges of its improvement are the synchronisation of warehouse layout, storage assignment policy, routing, zoning, and batching. Furthermore, the competitiveness of the warehouse depends on how it adapts to the unique customer demands and product parameters and the changes. The operators usually have to manage the picking sequence based on best practices taking into consideration the product stacking factors and minimising the lead time. It is usually necessary to support the operators by making e ective decisions. Researchers of the pallet loading problem, bin packing problem, and order picking optimisation provide a wide horizon of solutions but their results are rarely synchronised.

Using Robot Skills for Flexible Reprogramming of Pick Operations in Industrial Scenarios

DEFF Research Database (Denmark)

Andersen, Rasmus S.; Nalpantidis, Lazaros; Krüger, Volker

2014-01-01

objects on tabletops and pick them up in a user-specified manner. The programming itself is primarily done through kinesthetic teaching. We show that the skill has robustness towards the location and shape of the object to pick, and that objects from a real industrial production line can be handled. Also......, preliminary tests indicate that non-expert users can learn to use the skill after only a short introduction....

Estimation of mean-reverting oil prices: a laboratory approach

International Nuclear Information System (INIS)

Bjerksund, P.; Stensland, G.

1993-12-01

Many economic decision support tools developed for the oil industry are based on the future oil price dynamics being represented by some specified stochastic process. To meet the demand for necessary data, much effort is allocated to parameter estimation based on historical oil price time series. The approach in this paper is to implement a complex future oil market model, and to condense the information from the model to parameter estimates for the future oil price. In particular, we use the Lensberg and Rasmussen stochastic dynamic oil market model to generate a large set of possible future oil price paths. Given the hypothesis that the future oil price is generated by a mean-reverting Ornstein-Uhlenbeck process, we obtain parameter estimates by a maximum likelihood procedure. We find a substantial degree of mean-reversion in the future oil price, which in some of our decision examples leads to an almost negligible value of flexibility. 12 refs., 2 figs., 3 tabs

NMRNet: A deep learning approach to automated peak picking of protein NMR spectra.

Science.gov (United States)

Klukowski, Piotr; Augoff, Michal; Zieba, Maciej; Drwal, Maciej; Gonczarek, Adam; Walczak, Michal J

2018-03-14

Automated selection of signals in protein NMR spectra, known as peak picking, has been studied for over 20 years, nevertheless existing peak picking methods are still largely deficient. Accurate and precise automated peak picking would accelerate the structure calculation, and analysis of dynamics and interactions of macromolecules. Recent advancement in handling big data, together with an outburst of machine learning techniques, offer an opportunity to tackle the peak picking problem substantially faster than manual picking and on par with human accuracy. In particular, deep learning has proven to systematically achieve human-level performance in various recognition tasks, and thus emerges as an ideal tool to address automated identification of NMR signals. We have applied a convolutional neural network for visual analysis of multidimensional NMR spectra. A comprehensive test on 31 manually-annotated spectra has demonstrated top-tier average precision (AP) of 0.9596, 0.9058 and 0.8271 for backbone, side-chain and NOESY spectra, respectively. Furthermore, a combination of extracted peak lists with automated assignment routine, FLYA, outperformed other methods, including the manual one, and led to correct resonance assignment at the levels of 90.40%, 89.90% and 90.20% for three benchmark proteins. The proposed model is a part of a Dumpling software (platform for protein NMR data analysis), and is available at https://dumpling.bio/. michaljerzywalczak@gmail.compiotr.klukowski@pwr.edu.pl. Supplementary data are available at Bioinformatics online.

Interaction of intersteller pick-up ions with the solar wind

International Nuclear Information System (INIS)

Mobius, E.; Klecker, B.; Hovestadt, D.; Scholer, M.

1988-01-01

The interaction of interstellar pick-up ions with the solar wind is studied by comparing a model for the velocity distribution function of pick-up ions with actual measurements of He + ions in the solar wind. The model includes the effects of pitch-angle diffusion due to interplanetary Alfven waves, adiabatic deceleration in the expanding solar wind and the radial variation of the source function. It is demonstrated that the scattering mean free path is in the range ≤0.1 AU and that energy diffusion can be neglected as compared with adiabatic deceleration. The effects of adiabatic focusing, of the radial variation of the neutral density and of an variation of the solar wind velocity with distance from the Sun are investigated. With the correct choice of these parameters the authors can model the measured energy spectra of the pick-up ions does not vary with the solar wind velocity and the direction of the interplanetary magnetic field for a given local neutral gas density and ionization rate. Therefore, the comparison of the model distributions with the measurements leads to a quantitative determination of the local interstellar gas density

Derivatives of aminocyclitols, obtainment procedure and uses

OpenAIRE

Llebaria, Amadeu; Casas Brugulat, Josefina; Egido Gabás, Meritxell; Díaz Bueno, Lucía; Bujons Vilàs, Jordi

2009-01-01

[ES] La presente invención se refiere a los compuestos de fórmula general (I) y a sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de Tay-Sachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann- Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obtenció...

PICK1 uncoupling from mGluR7a causes absence-like seizures

OpenAIRE

Bertaso, Federica; Zhang, Chuansheng; Scheschonka, Astrid; de Bock, Frédéric; Fontanaud, Pierre; Marin, Philippe; Huganir, Richard L; Betz, Heinrich; Bockaert, Joël; Fagni, Laurent; Lerner-Natoli, Mireille

2008-01-01

Absence epilepsy is a neurological disorder that causes a recurrent loss of consciousness and generalized spike-and-wave discharges on an electroencephalogram (EEG). The role of metabotropic glutamate receptors (mGluRs) and associated scaffolding proteins in absence epilepsy has been unclear to date. We investigated a possible role for these proteins in absence epilepsy, focusing on the mGluR7a receptor and its PDZ-interacting protein, protein interacting with C kinase 1 (PICK1), in rats and ...

Molecular determinants for the complex binding specificity of the PDZ domain in PICK1

DEFF Research Database (Denmark)

Madsen, Kenneth L; Beuming, Thijs; Niv, Masha Y

2005-01-01

PICK1 (protein interacting with C kinase 1) contains a single PDZ domain known to mediate interaction with the C termini of several receptors, transporters, ion channels, and kinases. In contrast to most PDZ domains, the PICK1 PDZ domain interacts with binding sequences classifiable as type I (te...

The BAR Domain Protein PICK1 Controls Vesicle Number and Size in Adrenal Chromaffin Cells

DEFF Research Database (Denmark)

da Silva Pinheiro, Paulo César; Jansen, Anna M; de Wit, Heidi

2014-01-01

, a marker for immature granules. In chromaffin cells isolated from a PICK1 knockout (KO) mouse the amount of exocytosis was reduced, while release kinetics and Ca(2+) sensitivity were unaffected. Vesicle-fusion events had a reduced frequency and released lower amounts of transmitter per vesicle (i...... in vesicle number and size, whereas the fusion competence of generated vesicles was unaffected by the absence of PICK1. Viral rescue experiments demonstrated that long-term re-expression of PICK1 is necessary to restore normal vesicular content and secretion, while short-term overexpression is ineffective...

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

OpenAIRE

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2008-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redis...

Generalized fragment picking in Rosetta: design, protocols and applications.

Directory of Open Access Journals (Sweden)

Dominik Gront

Full Text Available The Rosetta de novo structure prediction and loop modeling protocols begin with coarse grained Monte Carlo searches in which the moves are based on short fragments extracted from a database of known structures. Here we describe a new object oriented program for picking fragments that greatly extends the functionality of the previous program (nnmake and opens the door for new approaches to structure modeling. We provide a detailed description of the code design and architecture, highlighting its modularity, and new features such as extensibility, total control over the fragment picking workflow and scoring system customization. We demonstrate that the program provides at least as good building blocks for ab-initio structure prediction as the previous program, and provide examples of the wide range of applications that are now accessible.

Vision guided robot bin picking of cylindrical objects

DEFF Research Database (Denmark)

Christensen, Georg Kronborg; Dyhr-Nielsen, Carsten

1997-01-01

In order to achieve increased flexibility on robotic production lines an investigation of the rovbot bin-picking problem is presented. In the paper, the limitations related to previous attempts to solve the problem are pointed uot and a set of innovative methods are presented. The main elements...

Metaheuristic approaches to order sequencing on a unidirectional picking line

Directory of Open Access Journals (Sweden)

AP de Villiers

2013-06-01

Full Text Available In this paper the sequencing of orders on a unidirectional picking line is considered. The aim of the order sequencing is to minimise the number of cycles travelled by a picker within the picking line to complete all orders. A tabu search, simulated annealing, genetic algorithm, generalised extremal optimisation and a random local search are presented as possible solution approaches. Computational results based on real life data instances are presented for these metaheuristics and compared to the performance of a lower bound and the solutions used in practise. The random local search exhibits the best overall solution quality, however, the generalised extremal optimisation approach delivers comparable results in considerably shorter computational times.

Material flow enhancement in production assembly lines under application of zoned order picking systems

Directory of Open Access Journals (Sweden)

D. Živanić

2014-10-01

Full Text Available Introduced research work relates to the possibility of material flow enhancement in production systems, with the apostrophe on material order picking in production assembly lines. The paper presents basic rules and the results related to formed computer models of zoned order picking systems under the application of developed bound cavities method.

Tracked "Pick-Up" Ultrasound for Robot-Assisted Minimally Invasive Surgery.

Science.gov (United States)

Schneider, Caitlin; Nguan, Christopher; Rohling, Robert; Salcudean, Septimiu

2016-02-01

We present a novel "pick-up" ultrasound transducer for intraabdominal robot-assisted minimally invasive surgery. Such a "pick-up" ultrasound transducer is inserted through an abdominal incision at the beginning of the procedure and remains in the abdominal cavity throughout, eliminating the need for a dedicated port or a patient bedside surgical assistant. The transducer has a handle that can be grasped in a repeatable manner using a da Vinci Prograsp tool, allowing the transducer to be accurately manipulated by the surgeon using the da Vinci Robot. This is one way to enable 3-D tracking of the transducer, and, thus, mapping of the vasculature. The 3-D vascular images can be used to register preoperative CT to intraoperative camera images. To demonstrate the feasibility of the approach, we use an ultrasound vessel phantom to register a CT surface model to extracted ultrasound vessel models. The 3-D vascular phantom images are generated by segmenting B-mode images and tracking the pick-up ultrasound transducer with the da Vinci kinematics, internal electromagnetic sensor, or visible fiducials suitable for camera tracking. Reconstruction results using da Vinci kinematics for tracking give a target registration error of 5.4 ± 1.7 mm.

Treatment of Chronic Skin-Picking in an Adolescent With Asperger Syndrome and Borderline Intellectual Disability

NARCIS (Netherlands)

Lang, R.B.; Didden, H.C.M.; Sigafoos, J.; Rispoli, M.; Regester, A.; Lancioni, G.E.

2009-01-01

We present the case of a 17-year-old girl with Asperger syndrome and borderline intellectual disability with a 5-year history of chronic skin-picking. Our intervention approach included an initial functional assessment to identify variables maintaining skin-picking, followed by evaluation of a

Excoriation (skin picking) disorder in Israeli University students

DEFF Research Database (Denmark)

Leibovici, Vera; Murad, Sari; Cooper-Kazaz, Rena

2014-01-01

, depression, obsessive-compulsive disorder, body dysmorphic disorder and disruptive, impulse control and conduct disorders. A total of 2176 participants (43.6%) responded and were included in the analysis. Mean age was 25.1 ± 4.8 (range 17-60) years, and 64.3% were female. RESULTS: The proportion of students...... who were screened positive for SPD was 3.03%, with a nearly equal gender distribution (3.0% in females and 3.1% in males). There was a trend toward significantly higher rates of psychiatric problems such as generalized anxiety, compulsive sexual behavior and eating disorders in these students. Within...... the group of students screening positive for SPD, alcohol intake was higher in male students, while female students perceived themselves as less attractive. No association was found between depression and SPD. A high prevalence rate of skin picking was found within first-degree family members...

Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice

DEFF Research Database (Denmark)

Christiansen, Søren Hofman Oliveira; Olesen, Mikkel Vestergaard; Wörtwein, Gitta

2011-01-01

Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression......-like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels...... in the medial amygdala. Concomitant FLX treatment reverted depression-like effects of CRS and led to significant increases in levels of NPY and galanin mRNA in the dentate gyrus, amygdala, and piriform cortex. These findings suggest that effects on NPY and galanin gene expression could play a role...

Sensitivity of Velocity Picking on 4th Order Non Hyperbolic Move out Correction

International Nuclear Information System (INIS)

Enuma, C.; Hope, R.; Idoko, P.

2003-01-01

Long offset processing has become the standard for TotaFinaElf in the Deep Offshore Nigeria. The advantage of having longer offsets are numerous; higher fold of coverage, improved S/N improved AVA analysis, less multiple contamination etc. A key element in successful long offset processing is the higher order velocity picking. In classical processing of seismic data with standard 2nd order terms for NMO correction, and outer mute at approximately 27 degrees, not to include non flattened events is required. By applying 3 terms 4th order anisotropic non hyperbolic corrections, angles out to 50-60 degrees may be flattened and can be very useful. Typically in modern 3D seismic data processing velocities are picked every 1km or 0.5km. a test was carried out to study the effect of the lateral velocity pick spacing required to properly flatten events at longer offsets. The evaluation of the test w3as carried out by loading all the CMP gathers along the line on a workstation as a 3D so that the flatness on pre-stack could be studied. The analysis showed that for 2nd order NMO 0.5km spacing is adequate to properly interpolate and flatten events at all CMP gathers along the line. However it was shown that for more advanced processing, such as the 4th order anisotropic three terms non hyperbolic velocity corrections, a more dense lateral velocity picking would be advantageous in terms of flattening of reflections. This presentation show how important long offset processing is and especially the importance of velocity picking

Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P

Directory of Open Access Journals (Sweden)

Lahey Cora

2006-08-01

Full Text Available Abstract Background Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA. We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P. The goal of this study was to clinically evaluate this assay. Methods Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. Results We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (ΨGBA due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. Conclusion Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that

Experimental Investigation of the Influence of Confining Stress on Hard Rock Fragmentation Using a Conical Pick

Science.gov (United States)

Li, Xibing; Wang, Shaofeng; Wang, Shanyong

2018-01-01

High geostress is a prominent condition in deep excavations and affects the cuttability of deep hard rock. This study aims to determine the influence of confining stress on hard rock fragmentation as applied by a conical pick. Using a true triaxial test apparatus, static and coupled static and dynamic loadings from pick forces were applied to end faces of cubic rock specimens to break them under biaxial, uniaxial and stress-free confining stress conditions. The cuttability indices (peak pick force, insertion depth and disturbance duration), failure patterns and fragment sizes were measured and compared to estimate the effects of confining stress. The results show that the rock cuttabilities decreased in order from rock breakages under stress-free conditions to uniaxial confining stress and then to biaxial confining stress. Under biaxial confining stress, only flake-shaped fragments were stripped from the rock surfaces under the requirements of large pick forces or disturbance durations. As the level of uniaxial confining stress increased, the peak pick force and the insertion depth initially increased and then decreased, and the failure patterns varied from splitting to partial splitting and then to rock bursts with decreasing average fragment sizes. Rock bursts will occur under elastic compression via ultra-high uniaxial confining stresses. There are two critical uniaxial confining stress levels, namely stress values at which peak pick forces begin to decrease and improve rock cuttability, and those at which rock bursts initially occur and cutting safety decreases. In particular, hard rock is easiest to split safely and efficiently under stress-free conditions. Moreover, coupled static preloading and dynamic disturbance can increase the efficiency of rock fragmentation with increasing preloading levels and disturbance amplitudes. The concluding remarks confirm hard rock cuttability using conical pick, which can improve the applicability of mechanical excavation in

Pick-N-Pull Auto Dismantlers, Kansas City, LLC Inc.

Science.gov (United States)

The EPA is providing notice of a proposed Administrative Penalty Assessment against Pick-N-Pull Auto Dismantlers, Kansas City, LLC, a subsidiary of Schnitzer Steel Industries, Inc., for alleged violations at its facilities at 8012 East Truman Rd., Kansas C

Single neutron pick-up on {sup 104}Pd

Energy Technology Data Exchange (ETDEWEB)

Rodrigues, M.R.D.; Andre, J.P.A.M. de; Borello-Lewin, T.; Horodynski-Matsushigue, L.B.; Duarte, J.L.M.; Rodrigues, C.L. [Universidade de Sao Paulo, SP (Brazil). Inst. de Fisica; Ukita, G.M. [Universidade de Santo Amaro, SP (Brazil). Faculdade de Psicologia

2006-12-15

Low-lying levels of {sup 103}Pd have been investigated through the (d,t) reaction on {sup 104}Pd, at an incident deuteron energy of 15.0 MeV. Outgoing particles were momentum analyzed by an Enge magnetic spectrograph and detected in nuclear emulsion plates, with an energy resolution of 8 keV. Previous (d,t) work suffered from a much worse resolution than that here achieved. A partial analysis of the data obtained is reported, referring to six out of the fourteen scattering angles for which data were obtained. Angular distributions associated with eight of the thirteen levels seen up to 1.1 MeV of excitation have been compared to DWBA one-neutron pick-up predictions. Both, the attributed excitation energy values and the transferred angular momenta are in excellent agreement with the results of other kind of experiments, as tabulated by the Nuclear Data Sheets. Some peculiar structure characteristics, associated with the yrast 5/2{sup +}, 3/2{sup +} and 7/2{sup +} states found in the Ru chain could be recognized also in {sup 103}Pd, pointing to the possibility of a more global understanding of this transitional mass region. (author)

3.3 Å structure of Niemann–Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport

Energy Technology Data Exchange (ETDEWEB)

Li, Xiaochun; Lu, Feiran; Trinh, Michael N.; Schmiege, Philip; Seemann, Joachim; Wang, Jiawei; Blobel, Günter

2017-08-07

Niemann–Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann–Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314–1,278), which—in contrast to previous lower resolution structures—features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909–C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD–NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

Comparison of radiation-induced proteins in two revertants with those in a radiation sensitive mutant of Deinococcus radiodurans

International Nuclear Information System (INIS)

Hu Qian; Tanaka, Atsushi; Kobayashi, Yasuhiko; Nozawa, Ranko; Watanabe, Hiroshi.

1992-01-01

In order to search proteins responsible for DNA repair, the intracellular proteins in gamma-irradiated cells of D.radiodurans R1 and its three mutants were analyzed by means of two-dimensional gel electrophoresis. Two new proteins, P35 (M.W. 35 kDa) and P92 (M.W. 92 kDa), were found in the cells of the radioresistant revertant (KH8401-1-5) and D.radiodurans R1. However, only P92 was detected in the moderately radioresistant revertant (KH8401-10-7). Both proteins were not detected in the cells of the radiosensitive mutant (KH8401). On the other hand, one protein, P25 (M.W. 25 kDa), which was detected either before or after gamma-irradiation, was only found in KH8401-10-7. These results suggest that these special induced proteins, P35 and P92, might be directly responsible for radiation resistance. The analyses of similar proteins in the cells of E.coli B/r and Deinobactor grandis KS0460 were also carried out. (author)

The Impact of Visual Guided Order Picking on Ocular Comfort, Ocular Surface and Tear Function.

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Angelika Klein-Theyer

Full Text Available We investigated the effects of a visual picking system on ocular comfort, the ocular surface and tear function compared to those of a voice guided picking solution.Prospective, observational, cohort study.Institutional.A total of 25 young asymptomatic volunteers performed commissioning over 10 hours on two consecutive days.The operators were guided in the picking process by two different picking solutions, either visually or by voice while their subjective symptoms and ocular surface and tear function parameters were recorded.The visual analogue scale (VAS values, according to subjective dry eye symptoms, in the visual condition were significantly higher at the end of the commissioning than the baseline measurements. In the voice condition, the VAS values remained stable during the commissioning. The tear break-up time (BUT values declined significantly in the visual condition (pre-task: 16.6 sec and post-task: 9.6 sec in the right eyes, that were exposed to the displays, the left eyes in the visual condition showed only a minor decline, whereas the BUT values in the voice condition remained constant (right eyes or even increased (left eyes over the time. No significant differences in the tear meniscus height values before and after the commissioning were observed in either condition.In our study, the use of visually guided picking solutions was correlated with post-task subjective symptoms and tear film instability.

DeepPicker: A deep learning approach for fully automated particle picking in cryo-EM.

Science.gov (United States)

Wang, Feng; Gong, Huichao; Liu, Gaochao; Li, Meijing; Yan, Chuangye; Xia, Tian; Li, Xueming; Zeng, Jianyang

2016-09-01

Particle picking is a time-consuming step in single-particle analysis and often requires significant interventions from users, which has become a bottleneck for future automated electron cryo-microscopy (cryo-EM). Here we report a deep learning framework, called DeepPicker, to address this problem and fill the current gaps toward a fully automated cryo-EM pipeline. DeepPicker employs a novel cross-molecule training strategy to capture common features of particles from previously-analyzed micrographs, and thus does not require any human intervention during particle picking. Tests on the recently-published cryo-EM data of three complexes have demonstrated that our deep learning based scheme can successfully accomplish the human-level particle picking process and identify a sufficient number of particles that are comparable to those picked manually by human experts. These results indicate that DeepPicker can provide a practically useful tool to significantly reduce the time and manual effort spent in single-particle analysis and thus greatly facilitate high-resolution cryo-EM structure determination. DeepPicker is released as an open-source program, which can be downloaded from https://github.com/nejyeah/DeepPicker-python. Copyright © 2016 Elsevier Inc. All rights reserved.

Association between periodontal diseases and systemic diseases

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Patrícia Weidlich

2008-08-01

Full Text Available Current evidence suggests that periodontal disease may be associated with systemic diseases. This paper reviewed the published data about the relationship between periodontal disease and cardiovascular diseases, adverse pregnancy outcomes, diabetes and respiratory diseases, focusing on studies conducted in the Brazilian population. Only a few studies were found in the literature focusing on Brazilians (3 concerning cardiovascular disease, 7 about pregnancy outcomes, 9 about diabetes and one regarding pneumonia. Although the majority of them observed an association between periodontitis and systemic conditions, a causal relationship still needs to be demonstrated. Further studies, particularly interventional well-designed investigations, with larger sample sizes, need to be conducted in Brazilian populations.

Dispatched and Scube Mediate the Efficient Secretion of the Cholesterol-Modified Hedgehog Ligand

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Hanna Tukachinsky

2012-08-01

Full Text Available The Hedgehog (Hh signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand.

Late endosomal cholesterol accumulation leads to impaired intra-endosomal trafficking.

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Komla Sobo

Full Text Available BACKGROUND: Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics. METHODOLOGY/PRINCIPAL FINDINGS: Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2-3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus. CONCLUSIONS/SIGNIFICANCE: These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation.

Intracellular sphingosine releases calcium from lysosomes.

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Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D; Platt, Frances M; Galione, Antony; Schultz, Carsten

2015-11-27

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

Amino acid substitutions in subunit 9 of the mitochondrial ATPase complex of Saccharomyces cerevisiae. Sequence analysis of a series of revertants of an oli1 mit- mutant carrying an amino acid substitution in the hydrophilic loop of subunit 9.

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Willson, T A; Nagley, P

1987-09-01

This work concerns a biochemical genetic study of subunit 9 of the mitochondrial ATPase complex of Saccharomyces cerevisiae. Subunit 9, encoded by the mitochondrial oli1 gene, contains a hydrophilic loop connecting two transmembrane stems. In one particular oli1 mit- mutant 2422, the substitution of a positively charged amino acid in this loop (Arg39----Met) renders the ATPase complex non-functional. A series of 20 revertants, selected for their ability to grow on nonfermentable substrates, has been isolated from mutant 2422. The results of DNA sequence analysis of the oli1 gene in each revertant have led to the recognition of three groups of revertants. Class I revertants have undergone a same-site reversion event: the mutant Met39 is replaced either by arginine (as in wild-type) or lysine. Class II revertants maintain the mutant Met39 residue, but have undergone a second-site reversion event (Asn35----Lys). Two revertants showing an oligomycin-resistant phenotype carry this same second-site reversion in the loop region together with a further amino acid substitution in either of the two membrane-spanning segments of subunit 9 (either Gly23----Ser or Leu53----Phe). Class III revertants contain subunit 9 with the original mutant 2422 sequence, and additionally carry a recessive nuclear suppressor, demonstrated to represent a single gene. The results on the revertants in classes I and II indicate that there is a strict requirement for a positively charged residue in the hydrophilic loop close to the boundary of the lipid bilayer. The precise location of this positive charge is less stringent; in functional ATPase complexes it can be found at either residue 39 or 35. This charged residue is possibly required to interact with some other component of the mitochondrial ATPase complex. These findings, together with hydropathy plots of subunit 9 polypeptides from normal, mutant and revertant strains, led to the conclusion that the hydrophilic loop in normal subunit 9

Effects of intracerebroventricular administration of 2-hydroxypropyl-β-cyclodextrin in a patient with Niemann–Pick Type C disease

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Muneaki Matsuo

2014-01-01

Full Text Available Niemann–Pick Type C disease (NPC is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood–brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

An assessment of the waterside corrosion and hydrogen pick-up in the zircaloy-2 pressure tubes of PHWR

International Nuclear Information System (INIS)

Sah, D.N.

1992-01-01

In view of the deleterious effect of hydriding on the operating life of zircaloy-2 pressure tubes in PHWRs there is an urgent need for the assessment of the status of the pressure tubes with respect to corrosion and hydrogen pick-up in the operating PHWRs. A model has been developed for analysing the waterside corrosion and hydrogen pick-up in the zircaloy-2 pressure tubes under reactor operating conditions. This model predicts the axial profiles of oxide layer thickness and hydrogen pick-up in the pressure tubes as a function of the operating time of the reactor. The prediction of hydrogen pick-up by the model in the F-10 pressure tube of RAPS-I have been found to be in good agreement with the measured value of hydrogen content. This report gives a brief description of the model and its predictions on the present status of hydrogen pick-up in the pressure tubes of lead reactor RAPS-II. (author). 6 refs., 5 figs., 2 tabs

Revisiting the theory of the evolution of pick-up ion distributions: magnetic or adiabatic cooling?

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H. J. Fahr

2007-01-01

Full Text Available We study the phasespace behaviour of heliospheric pick-up ions after the time of their injection as newly created ions into the solar wind bulk flow from either charge exchange or photoionization of interplanetary neutral atoms. As interaction with the ambient MHD wave fields we allow for rapid pitch angle diffusion, but for the beginning of this paper we shall neglect the effect of quasilinear or nonlinear energy diffusion (Fermi-2 acceleration induced by counterflowing ambient waves. In the up-to-now literature connected with the convection of pick-up ions by the solar wind only adiabatic cooling of these ions is considered which in the solar wind frame takes care of filling the gap between the injection energy and energies of the thermal bulk of solar wind ions. Here we reinvestigate the basics of the theory behind this assumption of adiabatic pick-up ion reactions and correlated predictions derived from it. We then compare it with the new assumption of a pure magnetic cooling of pick-up ions simply resulting from their being convected in an interplanetary magnetic field which decreases in magnitude with increase of solar distance. We compare the results for pick-up ion distribution functions derived along both ways and can point out essential differences of observational and diagnostic relevance. Furthermore we then include stochastic acceleration processes by wave-particle interactions. As we can show, magnetic cooling in conjunction with diffusive acceleration by wave-particle interaction allows for an unbroken power law with the unique power index γ=−5 beginning from lowest velocities up to highest energy particles of about 100 KeV which just marginally can be in resonance with magnetoacoustic turbulences. Consequences for the resulting pick-up ion pressures are also analysed.

Revisiting the theory of the evolution of pick-up ion distributions: magnetic or adiabatic cooling?

Directory of Open Access Journals (Sweden)

H. J. Fahr

2008-01-01

Full Text Available We study the phasespace behaviour of heliospheric pick-up ions after the time of their injection as newly created ions into the solar wind bulk flow from either charge exchange or photoionization of interplanetary neutral atoms. As interaction with the ambient MHD wave fields we allow for rapid pitch angle diffusion, but for the beginning of this paper we shall neglect the effect of quasilinear or nonlinear energy diffusion (Fermi-2 acceleration induced by counterflowing ambient waves. In the up-to-now literature connected with the convection of pick-up ions by the solar wind only adiabatic cooling of these ions is considered which in the solar wind frame takes care of filling the gap between the injection energy and energies of the thermal bulk of solar wind ions. Here we reinvestigate the basics of the theory behind this assumption of adiabatic pick-up ion reactions and correlated predictions derived from it. We then compare it with the new assumption of a pure magnetic cooling of pick-up ions simply resulting from their being convected in an interplanetary magnetic field which decreases in magnitude with increase of solar distance. We compare the results for pick-up ion distribution functions derived along both ways and can point out essential differences of observational and diagnostic relevance. Furthermore we then include stochastic acceleration processes by wave-particle interactions. As we can show, magnetic cooling in conjunction with diffusive acceleration by wave-particle interaction allows for an unbroken power law with the unique power index γ=−5 beginning from lowest velocities up to highest energy particles of about 100 KeV which just marginally can be in resonance with magnetoacoustic turbulences. Consequences for the resulting pick-up ion pressures are also analysed.

CONEDEP: COnvolutional Neural network based Earthquake DEtection and Phase Picking

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Zhou, Y.; Huang, Y.; Yue, H.; Zhou, S.; An, S.; Yun, N.

2017-12-01

We developed an automatic local earthquake detection and phase picking algorithm based on Fully Convolutional Neural network (FCN). The FCN algorithm detects and segments certain features (phases) in 3 component seismograms to realize efficient picking. We use STA/LTA algorithm and template matching algorithm to construct the training set from seismograms recorded 1 month before and after the Wenchuan earthquake. Precise P and S phases are identified and labeled to construct the training set. Noise data are produced by combining back-ground noise and artificial synthetic noise to form the equivalent scale of noise set as the signal set. Training is performed on GPUs to achieve efficient convergence. Our algorithm has significantly improved performance in terms of the detection rate and precision in comparison with STA/LTA and template matching algorithms.

The image, medium and objective in the painter of battles of Arturo Perez Reverte

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Virginia Isla García

2009-02-01

Full Text Available The essay's purpose is to contemplate the relationship between the image (as an experience and as a memory as well as its role and exposure in El pintor de batallas', a story written by Arturo Pérez-Reverte (2006. Supporting our statements in the text, we will deduce this relationship to have as the main consequences the assumed limits of the space and time, as well as the creation, with the resources and constructions of the fiction, of a fragmented and subjective image that the reader will need to rebuild to better perceive the universality the novel aims at.

Investigation into the potential for dust and gas explosions in underground coal mines with reference to pick tip geometry

International Nuclear Information System (INIS)

Dawood, Albert D.

2011-01-01

In underground coal mines, methane gas, if present in sufficient concentration, may be ignited by sparks from hot spots on the picks of coal cutting machines striking hard bands of rock. During the coal cutting, wear-flat areas develop on the trailing side of the tips of picks. As pick wear progresses, the generation of frictional heat and coal dust increases and the development of hot spots at the cutting tips may lead to an explosion of methane gas. Field experience and research work over the last few years have facilitated excellent cutting performance for certain picks through the optimisation of the cutting parameters. Such performance improvements show great promise in preventing the incidence of gas or dust explosions occurring at the coal face area. This study sets out some of the fundamentals of pick geometry and cutting parameters and the methods which have been employed to achieve improvements in reducing the hazards of gas or dust explosions. It is based on the comparative trial results of two types of picks with different designs and on a range of available research information on the subject. My investigation looked at the fundamentals of pick geometry and cutting parameters and the current suppression techniques in place to control the dust and gas explosions on the coal operating face.

Functional Assessment and Behavioral Treatment of Skin Picking in a Teenage Girl With Prader-Willi Syndrome

NARCIS (Netherlands)

Radstaake, M.; Didden, H.C.M.; Bolio, M.M.L.; Lang, R.B.; Lancioni, G.E.; Curfs, L.M.G.

2011-01-01

Skin picking is common in individuals with Prader-Willi Syndrome (PWS) but few treatment studies exist. This study reports the successful functional behavioral assessment (FBA) and treatment of skin picking in a 16-year-old female with PWS. A treatment package based on FBA results consisted of

A Robust Formant Extraction Algorithm Combining Spectral Peak Picking and Root Polishing

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Seo Kwang-deok

2006-01-01

Full Text Available We propose a robust formant extraction algorithm that combines the spectral peak picking, formants location examining for peak merger checking, and the root extraction methods. The spectral peak picking method is employed to locate the formant candidates, and the root extraction is used for solving the peak merger problem. The location and the distance between the extracted formants are also utilized to efficiently find out suspected peak mergers. The proposed algorithm does not require much computation, and is shown to be superior to previous formant extraction algorithms through extensive tests using TIMIT speech database.

An intelligent identification algorithm for the monoclonal picking instrument

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Yan, Hua; Zhang, Rongfu; Yuan, Xujun; Wang, Qun

2017-11-01

The traditional colony selection is mainly operated by manual mode, which takes on low efficiency and strong subjectivity. Therefore, it is important to develop an automatic monoclonal-picking instrument. The critical stage of the automatic monoclonal-picking and intelligent optimal selection is intelligent identification algorithm. An auto-screening algorithm based on Support Vector Machine (SVM) is proposed in this paper, which uses the supervised learning method, which combined with the colony morphological characteristics to classify the colony accurately. Furthermore, through the basic morphological features of the colony, system can figure out a series of morphological parameters step by step. Through the establishment of maximal margin classifier, and based on the analysis of the growth trend of the colony, the selection of the monoclonal colony was carried out. The experimental results showed that the auto-screening algorithm could screen out the regular colony from the other, which meets the requirement of various parameters.

Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K.

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Yamanashi, Yoshihide; Takada, Tappei; Kurauchi, Ryoya; Tanaka, Yusuke; Komine, Toko; Suzuki, Hiroshi

2017-04-03

Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies.

Relationship between concussion history and neurocognitive test performance in National Football League draft picks.

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Solomon, Gary S; Kuhn, Andrew

2014-04-01

There are limited empirical data available regarding the relationship between concussion history and neurocognitive functioning in active National Football League (NFL) players in general and NFL draft picks in particular. Potential NFL draft picks undergo 2 neurocognitive tests at the National Invitational Camp (Scouting Combine) every year: the Wonderlic and, since 2011, the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). After conclusion of the combine and before the draft, NFL teams invite potential draft picks to their headquarters for individual visits where further assessment may occur. To examine the relationship between concussion history and neurocognitive performance (ImPACT and Wonderlic) in a sample of elite NFL draft picks. Cohort study; Level of evidence, 3. Over 7 years, 226 potential draft picks were invited to visit a specific NFL team's headquarters after the combine. The athletes were divided into 3 groups based on self-reported concussion history: no prior concussions, 1 prior concussion, and 2 or more prior concussions. Neurocognitive measures of interest included Wonderlic scores (provided by the NFL team) and ImPACT composite scores (administered either at the combine or during a visit to the team headquarters). The relationship between concussion history and neurocognitive scores was assessed, as were the relationships among the 2 neurocognitive tests. Concussion history had no relationship to neurocognitive performance on either the Wonderlic or ImPACT. Concussion history did not affect performance on either neurocognitive test, suggesting that for this cohort, a history of concussion may not have adverse effects on neurocognitive functioning as measured by these 2 tests. This study reveals no correlation between concussion history and neurocognitive test scores (ImPACT, Wonderlic) in soon-to-be active NFL athletes.

SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease

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Jiyung Shin

2013-11-01

Full Text Available Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

Wavefront picking for 3D tomography and full-waveform inversion

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AlTheyab, Abdullah; Schuster, Gerard T.

2016-01-01

We have developed an efficient approach for picking firstbreak wavefronts on coarsely sampled time slices of 3D shot gathers. Our objective was to compute a smooth initial velocity model for multiscale full-waveform inversion (FWI). Using

A modeling of dynamic storage assignment for order picking in beverage warehousing with Drive-in Rack system

Science.gov (United States)

Hadi, M. Z.; Djatna, T.; Sugiarto

2018-04-01

This paper develops a dynamic storage assignment model to solve storage assignment problem (SAP) for beverages order picking in a drive-in rack warehousing system to determine the appropriate storage location and space for each beverage products dynamically so that the performance of the system can be improved. This study constructs a graph model to represent drive-in rack storage position then combine association rules mining, class-based storage policies and an arrangement rule algorithm to determine an appropriate storage location and arrangement of the product according to dynamic orders from customers. The performance of the proposed model is measured as rule adjacency accuracy, travel distance (for picking process) and probability a product become expiry using Last Come First Serve (LCFS) queue approach. Finally, the proposed model is implemented through computer simulation and compare the performance for different storage assignment methods as well. The result indicates that the proposed model outperforms other storage assignment methods.

Study on store-space assignment based on logistic AGV in e-commerce goods to person picking pattern

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Xu, Lijuan; Zhu, Jie

2017-10-01

This paper studied on the store-space assignment based on logistic AGV in E-commerce goods to person picking pattern, and established the store-space assignment model based on the lowest picking cost, and design for store-space assignment algorithm after the cluster analysis based on similarity coefficient. And then through the example analysis, compared the picking cost between store-space assignment algorithm this paper design and according to item number and storage according to ABC classification allocation, and verified the effectiveness of the design of the store-space assignment algorithm.

Public participation: Picking the players

International Nuclear Information System (INIS)

McNeill, L.; Jernigan, G.

1995-01-01

When citizens become involved in the public policy decision-making process, who picks the players? Are there any criteria for determining which members of the public should sit at the table? These are questions frequently asked by new participants and observers of the public involvement process. In the interest of trust and credibility, the process must be one of self-selection. Any exclusion on the part of the sponsoring organization would probably be interpreted by the public and the press as manipulative self-interest. Clearly, at times there are irrational people attending public meetings or submitting written comments. But if an organization begins excluding participants, the risk increases that the process will be perceived as a travesty

High-lying neutron hole strengths observed in pick-up reactions

International Nuclear Information System (INIS)

Gales, S.

1980-01-01

Neutron-hole states in orbits well below the Fermi surface have been observed in a number of medium-heavy nuclei from A=90 to 209 using one nucleon pick-up reactions. The excitation energies, angular distributions of such broad and enhanced structures will be discussed. The fragmentation of the neutron-hole strengths as well as the spreading of such simple mode of excitations into more complex states are compared to recent calculations within the quasiparticle-phonon or the single particle-vibration coupling nuclear models. We report on recent measurements of J for inner-hole states in 89 Zr and 115 Sn 119 Sn using the analyzing power of the (p,d) and (d,t) reactions. Large enhancement of cross-sections are observed at high excitation energy in the study of the (p,t) reactions on Zr, Cd, Sn, Te and Sm isotopes. The systematic features of such high-lying excitation are related to the ones observed in one neutron pick-up experiments. The origin of such concentration of two neutron-hole strengths in Cd and Sn isotopes will be discussed. Preliminary results obtained in the study of the (α, 6 He) reaction at 218 MeV incident energy on 90 Zr, 118 Sn and 208 Pb targets are presented and compared to the (p,t) results. Finally the properties of hole-analog states populated in neutron pick-up reactions (from 90 Zr to 208 Pb) will be presented

The Lifestyle Carbon Dividend: Assessment of the Carbon Sequestration Potential of Grasslands and Pasturelands Reverted to Native Forests

Science.gov (United States)

Rao, S.; Jain, A. K.; Shu, S.

2015-12-01

What is the potential of a global transition to a vegan lifestyle to sequester carbon and mitigate climate change? To answer this question, we use an Earth System Model (ESM), the Integrated Science Assessment Model (ISAM). ISAM is a fully coupled biogeochemistry (carbon and nitrogen cycles) and biogeophysics (hydrology and thermal energy) ESM, which calculates carbon sources and sinks due to land cover and land use change activities, such as reforestation and afforestation. We calculate the carbon sequestration potential of grasslands and pasturelands that can be reverted to native forests as 265 GtC on 1.96E+7 km2 of land area, just 41% of the total area of such lands on Earth. The grasslands and pasturelands are assumed to revert back to native forests which existed prior to any human intervention and these include tropical, temperate and boreal forests. The results are validated with above ground regrowth measurements. Since this carbon sequestration potential is greater than the 240 GtC of that has been added to the atmosphere since the industrial era began, it shows that such global lifestyle transitions have tremendous potential to mitigate and even reverse climate change.

Pick- and waveform-based techniques for real-time detection of induced seismicity

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Grigoli, Francesco; Scarabello, Luca; Böse, Maren; Weber, Bernd; Wiemer, Stefan; Clinton, John F.

2018-05-01

The monitoring of induced seismicity is a common operation in many industrial activities, such as conventional and non-conventional hydrocarbon production or mining and geothermal energy exploitation, to cite a few. During such operations, we generally collect very large and strongly noise-contaminated data sets that require robust and automated analysis procedures. Induced seismicity data sets are often characterized by sequences of multiple events with short interevent times or overlapping events; in these cases, pick-based location methods may struggle to correctly assign picks to phases and events, and errors can lead to missed detections and/or reduced location resolution and incorrect magnitudes, which can have significant consequences if real-time seismicity information are used for risk assessment frameworks. To overcome these issues, different waveform-based methods for the detection and location of microseismicity have been proposed. The main advantages of waveform-based methods is that they appear to perform better and can simultaneously detect and locate seismic events providing high-quality locations in a single step, while the main disadvantage is that they are computationally expensive. Although these methods have been applied to different induced seismicity data sets, an extensive comparison with sophisticated pick-based detection methods is still missing. In this work, we introduce our improved waveform-based detector and we compare its performance with two pick-based detectors implemented within the SeiscomP3 software suite. We test the performance of these three approaches with both synthetic and real data sets related to the induced seismicity sequence at the deep geothermal project in the vicinity of the city of St. Gallen, Switzerland.

A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses.

Science.gov (United States)

Wec, Anna Z; Nyakatura, Elisabeth K; Herbert, Andrew S; Howell, Katie A; Holtsberg, Frederick W; Bakken, Russell R; Mittler, Eva; Christin, John R; Shulenin, Sergey; Jangra, Rohit K; Bharrhan, Sushma; Kuehne, Ana I; Bornholdt, Zachary A; Flyak, Andrew I; Saphire, Erica Ollmann; Crowe, James E; Aman, M Javad; Dye, John M; Lai, Jonathan R; Chandran, Kartik

2016-10-21

There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope. Bispecific antibodies, but not parent mAbs, neutralized all known ebolaviruses by coopting viral particles themselves for endosomal delivery and conferred postexposure protection against multiple ebolaviruses in mice. Such "Trojan horse" bispecific antibodies have potential as broad antifilovirus immunotherapeutics. Copyright © 2016, American Association for the Advancement of Science.

Application Value of Slider-Crank Mechanism in Pick-and-Place Operation of Delta Robot

Directory of Open Access Journals (Sweden)

Zhe QIN

2018-01-01

Full Text Available By absorbing the advantages of the rotary-driven Delta robot and linear-driven Delta robot, a Delta robot for pick-and-place operation that forms a crank-slider at the drive joint is designed.To take the most common gate shaped curve in Cartesian space as the motion trail of robotic pick-and-place operation, according to the kinematics inverse solution theory of Delta robot, this thesis mainly solves the output angular velocity of robot-driven joint. Establishing the static transfer mathematical model and solving the forced condition of driving joint. The simulation analysis show that after the upper slider-crank mechanism is connected to the driving joint, the angular velocity of the driving joint changes suddenly, which caused a rigid impact on the robot in the picking and releasing operation, though the force of the driving joint can be made smaller.

Wear Assessment of Conical Pick used in Coal Cutting Operation

Czech Academy of Sciences Publication Activity Database

Dewangan, S.; Chattopadhyaya, S.; Hloch, Sergej

-, 11/2014 (2014), s. 1-6 ISSN 0723-2632 Institutional support: RVO:68145535 Keywords : conical pick * wear * SEM * EDX Subject RIV: JQ - Machines ; Tools Impact factor: 2.420, year: 2014 http://link.springer.com/article/10.1007/s00603-014-0680-z

Proposal of an efficient operation method about order processing sequence and allocating goods to racks in the automatic picking system; Jido picking system ni okeru shohin no tanawaritsuke to chumon shori junjo no koritsuka un`yo hoshiki no teian

Energy Technology Data Exchange (ETDEWEB)

Ono, T.; Kagami, A.; Kosaka, M. [Hitachi Ltd., Tokyo (Japan)

1997-07-05

The material distribution center is a facility to store the goods from a factory and to prepare to ship the goods in response to order from retail store. Recently, with multiplication of consumption market, multi-variety and less-amount of the goods, multi-frequency of delivery and time saving form order to delivery are required. As picking work to prepare the stored goods for each customer requires specially many man-hours out of the works in this center, time saving of working becomes an important problem. In this paper, for an object of the automatic picking system constructed by plural equipments and to execute picking of small goods for each order, the following two operation methods were proposed: (1) To define shelf sharing of the goods so that the picking requirement numbers for each picking hand may be uniform as well as possible in response to order distribution for each goods, and (2) to define treating sequence of order so as not to generate large difference in order treating times among each treating hand on operation in parallel. These operation methods were confirmed their total treating time saving by some experiments using actual ordered data. 7 refs., 8 figs., 6 tabs.

Gamma-radiation Mutagenesis in Genetically Unstable Barley Mutants. Pt. 1. Chlorophyll Mutations in Allelic tw Mutants and Their Revertants

International Nuclear Information System (INIS)

Vaitkuniene, V.

1995-01-01

Genotypical environment is an essential factor determining the mutability of mutants of the same type. Decreased chlorophyll mutant frequency was a common characteristic of all tested tw type (tw, tw 1 , tw 2 ) mutants induced in barley c. 'Auksiniai II'. The mutability of all the tested revertants was close to that of the initial c. 'Auksiniai II'. (author). 9 refs., 2 tabs

77 FR 40385 - Withdrawal of Regulatory Guide 7.3; Procedures for Picking Up and Receiving Packages of...

Science.gov (United States)

2012-07-09

... Picking Up and Receiving Packages of Radioactive Material AGENCY: Nuclear Regulatory Commission. ACTION.... Nuclear Regulatory Commission (NRC or Commission) is withdrawing RG 7.3, ``Procedures for Picking Up and... Public Document Room (PDR) reference staff at 1-800-397-4209, or 301-415-4737, or by email at PDR...

Automatic seed picking for brachytherapy postimplant validation with 3D CT images.

Science.gov (United States)

Zhang, Guobin; Sun, Qiyuan; Jiang, Shan; Yang, Zhiyong; Ma, Xiaodong; Jiang, Haisong

2017-11-01

Postimplant validation is an indispensable part in the brachytherapy technique. It provides the necessary feedback to ensure the quality of operation. The ability to pick implanted seed relates directly to the accuracy of validation. To address it, an automatic approach is proposed for picking implanted brachytherapy seeds in 3D CT images. In order to pick seed configuration (location and orientation) efficiently, the approach starts with the segmentation of seed from CT images using a thresholding filter which based on gray-level histogram. Through the process of filtering and denoising, the touching seed and single seed are classified. The true novelty of this approach is found in the application of the canny edge detection and improved concave points matching algorithm to separate touching seeds. Through the computation of image moments, the seed configuration can be determined efficiently. Finally, two different experiments are designed to verify the performance of the proposed approach: (1) physical phantom with 60 model seeds, and (2) patient data with 16 cases. Through assessment of validated results by a medical physicist, the proposed method exhibited promising results. Experiment on phantom demonstrates that the error of seed location and orientation is within ([Formula: see text]) mm and ([Formula: see text])[Formula: see text], respectively. In addition, the most seed location and orientation error is controlled within 0.8 mm and 3.5[Formula: see text] in all cases, respectively. The average process time of seed picking is 8.7 s per 100 seeds. In this paper, an automatic, efficient and robust approach, performed on CT images, is proposed to determine the implanted seed location as well as orientation in a 3D workspace. Through the experiments with phantom and patient data, this approach also successfully exhibits good performance.

N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells

Directory of Open Access Journals (Sweden)

Ángel G. Valdivieso

2018-06-01

Full Text Available Chronic obstructive pulmonary disease (COPD and cystic fibrosis (CF are lethal pulmonary diseases. Cigarette consumption is the main cause for development of COPD, while CF is produced by mutations in the CFTR gene. Although these diseases have a different etiology, both share a CFTR activity impairment and proinflammatory state even under sterile conditions. The aim of this work was to study the extent of the protective effect of the antioxidant N-acetylcysteine (NAC over the proinflammatory state (IL-6 and IL-8, oxidative stress (reactive oxygen species, ROS, and CFTR levels, caused by Cigarette Smoke Extract (CSE in Calu-3 airway epithelial cells. CSE treatment (100 µg/ml during 24 h decreased CFTR mRNA expression and activity, and increased the release of IL-6 and IL-8. The effect on these cytokines was inhibited by N-acetyl cysteine (NAC, 5 mM or the NF-kB inhibitor, IKK-2 (10 µM. CSE treatment also increased cellular and mitochondrial ROS levels. The cellular ROS levels were normalized to control values by NAC treatment, although significant effects on mitochondrial ROS levels were observed only at short times (5´ and effects on CFTR levels were not observed. In addition, CSE reduced the mitochondrial NADH-cytochrome c oxidoreductase (mCx I-III activity, an effect that was not reverted by NAC. The reduced CFTR expression and the mitochondrial damage induced by CSE could not be normalized by NAC treatment, evidencing the need for a more specific reagent. In conclusion, CSE causes a sterile proinflammatory state and mitochondrial damage in Calu-3 cells that was partially recovered by NAC treatment. Keywords: Cigarette smoke extract, Mitochondria, CFTR, ROS, COPD, Cystic fibrosis

77 FR 36017 - Regulatory Guide 7.3, Procedures for Picking Up and Receiving Packages of Radioactive Material

Science.gov (United States)

2012-06-15

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0139] Regulatory Guide 7.3, Procedures for Picking Up and... Guide (RG) 7.3, ``Procedures for Picking Up and Receiving Packages of Radioactive Material.'' The guide..., please contact the NRC's Public Document Room (PDR) reference staff at 1-800-397-4209, or 301-415-4737...

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

Science.gov (United States)

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

How consumers pick a hotel strategic segmentation and target marketing

CERN Document Server

Winston, William

2013-01-01

Venture through the pages of How Consumers Pick a Hotel to learn the steps of selecting a target and using consumer behavior applications to segment the market to reach your target. Much as a consumer goes through the process of selecting a satisfying hotel, you can choose to use the information provided to make your hospitality career relaxing and satisfying. When you finish this fantastic reading journey, you'll be prepared to offer services that meet the public's demands, and you'll possess the prerequisite knowledge and skills for developing your own strategic approach to a target market. As the many methods of segmentation are discussed in detail, you will also learn effective strategies for communicating with multiple segments. Ideal as a supplementary text for marketing and hospitality marketing courses, How Consumers Pick a Hotel provides a concise overview of consumer behavior and intertwines marketing theory with sound ways in which to implement the theory. This will both orient you and give you a s...

MgB2 magnetometer with directly coupled pick-up loop

NARCIS (Netherlands)

Portesi, C.; Mijatovic, D.; Veldhuis, Dick; Brinkman, Alexander; Monticone, E.; Gonnelli, R.S.

2006-01-01

magnetometer with a directly coupled pick-up loop. We used an all in situ technique for fabricating magnesium diboride films, which consists of the co-evaporation of B and Mg by means of an e-gun and a resistive heater respectively. Consequently, we realized the superconducting device, which

An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1.

Science.gov (United States)

Herlo, Rasmus; Lund, Viktor K; Lycas, Matthew D; Jansen, Anna M; Khelashvili, George; Andersen, Rita C; Bhatia, Vikram; Pedersen, Thomas S; Albornoz, Pedro B C; Johner, Niklaus; Ammendrup-Johnsen, Ina; Christensen, Nikolaj R; Erlendsson, Simon; Stoklund, Mikkel; Larsen, Jannik B; Weinstein, Harel; Kjærulff, Ole; Stamou, Dimitrios; Gether, Ulrik; Madsen, Kenneth L

2018-05-15

BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N-terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin-producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation. This was accompanied by reduced hormone storage in the INS-1E cells. In Drosophila, disruption of the helix compromised growth regulation. By demonstrating size-dependent binding on insulin granules, our finding highlights the function of MCS for BAR domain proteins in a biological context distinct from their function, e.g., at the plasma membrane during endocytosis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Automatic picking of direct P, S seismic phases and fault zone head waves

Science.gov (United States)

Ross, Z. E.; Ben-Zion, Y.

2014-10-01

We develop a set of algorithms for automatic detection and picking of direct P and S waves, as well as fault zone head waves (FZHW), generated by earthquakes on faults that separate different lithologies and recorded by local seismic networks. The S-wave picks are performed using polarization analysis and related filters to remove P-wave energy from the seismograms, and utilize STA/LTA and kurtosis detectors in tandem to lock on the phase arrival. The early portions of P waveforms are processed with STA/LTA, kurtosis and skewness detectors for possible first-arriving FZHW. Identification and picking of direct P and FZHW is performed by a multistage algorithm that accounts for basic characteristics (motion polarities, time difference, sharpness and amplitudes) of the two phases. The algorithm is shown to perform well on synthetic seismograms produced by a model with a velocity contrast across the fault, and observed data generated by earthquakes along the Parkfield section of the San Andreas fault and the Hayward fault. The developed techniques can be used for systematic processing of large seismic waveform data sets recorded near major faults.

Interactive Micromanipulation of Picking and Placement of Nonconductive Microsphere in Scanning Electron Microscope

Directory of Open Access Journals (Sweden)

Ning Cao

2017-08-01

Full Text Available In this paper, classified theoretical models, consisting of contact with and placement of microsphere and picking operations, are simplified and established to depict the interactive behaviors of external and internal forces in pushing manipulations, respectively. Sliding and/or rolling cases, resulting in the acceleration of micromanipulations, are discussed in detail. Effective contact detection is achieved by combining alterations of light-shadow and relative movement displacement between the tip-sphere. Picking operations are investigated by typical interactive positions and different end tilt angles. Placements are realized by adjusting the proper end tilt angles. These were separately conducted to explore the interactive operations of nonconductive glass microspheres in a scanning electron microscope. The experimental results demonstrate that the proposed contact detection method can efficiently protect the end-tip from damage, regardless of operator skills in initial positioning operations. E-beam irradiation onto different interactive positions with end tilt angles can be utilized to pick up microspheres without bending the end-tip. In addition, the results of releasing deviations away from the pre-setting point were utilized to verify the effectiveness of the placement tilt angles.

(p, α) reactions: knock-on(out) or pick-up

International Nuclear Information System (INIS)

Gadioli, E.

1983-01-01

Nothwithstanding the great lot of data collected starting from the beginning of fifties, it cannot be said that a good degree of knowledge about the (p, α) reaction mechanism has been reached. Experimental data are usually interpreted or on the basis of a pure pick-up or knock-on(out) mechanism, though many results suggest the importance of both mechanism

Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases

OpenAIRE

Adnan, Humaira; Zhang, Zhenbo; Park, Hyun-Joo; Tailor, Chetankumar; Che, Clare; Kamani, Mustafa; Spitalny, George; Binnington, Beth; Lingwood, Clifford

2016-01-01

Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subu...

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells.

Science.gov (United States)

Bianchini, Francesca; Peppicelli, Silvia; Fabbrizzi, Pierangelo; Biagioni, Alessio; Mazzanti, Benedetta; Menchi, Gloria; Calorini, Lido; Pupi, Alberto; Trabocchi, Andrea

2017-01-01

Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.

Order picking in carousel systems under the nearest item heuristic

NARCIS (Netherlands)

Litvak, Nelli; Zijm, Willem H.M.; Adan, I.J.B.F.; Wessels, J.

2001-01-01

A carousel is a computer-controlled warehousing system, which is widely used to store small- and medium-sized goods. One of the most important performance characteristics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel. In this article, we

Order picking in carousel systems under the nearest item heuristic

NARCIS (Netherlands)

Litvak, Nelli; Adan, I.J.B.F.; Wessels, J.; Zijm, Willem H.M.

2000-01-01

A carousel is a computer controlled warehousing system, which is widely used to store small and medium sized goods. One of the most important performance characteristics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel. In this paper we consider

Order picking in carousel systems under the nearest item heuristic

NARCIS (Netherlands)

Litvak, Nelli; Adan, I.J.B.F.; Wessels, J.B.; Zijm, Willem H.M.

2001-01-01

A carousel is a computer-controlled warehousing system, which is widely used to store small- and medium-sized goods+ One of the most important performance character- istics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel+ In this article, we

The Effect of Slot-Code Optimization in Warehouse Order Picking

Directory of Open Access Journals (Sweden)

Andrea Fumi

2013-07-01

most appropriate material handling resource configuration. Building on previous work on the effect of slot-code optimization on travel times in single/dual command cycles, the authors broaden the scope to include the most general picking case, thus widening the range of applicability and realising former suggestions for future research.

Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients

NARCIS (Netherlands)

K. Theys (Kristof); K. Deforche; J. Vercauteren (Jurgen); P. Libin (Pieter); D.A.M.C. van de Vijver (David); J. Albert (Jan); B. Åsjö (Birgitta); M. Bruckova (Marie); R.J. Camacho (Ricardo Jorge); B. Clotet (Bonaventura); Z. Grossman (Zehava); A. Horban (Andrzej); C. Kücherer (Claudia); D. Paraskevis (Dimitrios); E. Puchhammer-Stöckl (Elisabeth); C. Riva (Chiara); L. Ruiz (Lidia); J.-C. Schmit (Jean-Claude); R. Schuurman (Rob); A. Sonnerborg (Anders); D. Stanekova (Danica); D. Struck (Daniel); K. van Laethem (Kristel); A.M.J. Wensing (Annemarie); E. Puchhammer-Stockl E. (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.M. Vandamme (Anne Mieke); I. Derdelinck (Inge); A. Sasse (A.); M. Bogaert (M.); H. Ceunen (H.); A. de Roo (Annie); M. De Wit (Meike); F. Echahidi (F.); K. Fransen (K.); J.-C. Goffard (J.); P. Goubau (Patrick); E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor (Patrick); C. Liesnard (C.); M. Moutschen (M.); L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira (D.); A. van den Heuvel (A.); B. van der Gucht (B.); M. van Ranst (Marc); E. van Wijngaerden (Eric); T. Vandercam; M. Vekemans (M.); C. Verhofstede; N. Clumeck (N.); K. van Laethem (K.); L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka (Marek); L. Machala (L.); L.B. Jrgensen (L.); J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); C. Nielsen (Claus); A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni (J.); J. Sutinen (J.); K. Korn (Klaus); C. K̈ucherer (C.); P. Braun (P.); G. Poggensee (G.); M. Däumer (M.); D. Eberle (David); O. Hamouda (Osamah); H. Heiken (H.); R. Kaiser (Rolf); H. Knechten (H.); H. M̈uller (H.); S. Neifer (S.); H. Walter (Hauke); B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); A. Hatzakis (Angelos); E. Hatzitheodorou (E.); C. Issaris (C.); C. Haida (C.); A. Zavitsanou (A.); G. Magiorkinis (Gkikas); M. Lazanas (M.); L. Chini; N. Magafas (N.); N. Tsogas (N.); V. Paparizos (V.); S. Kourkounti (S.); A. Antoniadou (A.); A. Papadopoulos (A.); P. Panagopoulos (P.); G. Poulakou (G.); V. Sakka (V.); G. Chryssos (G.); S. Drimis (S.); P. Gargalianos (P.); M. Lelekis (M.); G. Xilomenos (G.); M. Psichogiou (M.); G.L. Daikos (George); G. Panos (G.); G. Haratsis (G.); T. Kordossis (T.); A. Kontos (Angelos); G. Koratzanis (G.); M. Theodoridou (M.); G. Mostrou (G.); V. Spoulou (V.); W. Hall (W.); C. de Gascun (Cillian); C. Byrne (C.); M. Duffy (M.); P. Bergin; D. Reidy (D.); G. Farrell; J. Lambert (Julien); E. O'Connor (E.); A. Rochford (A.); J. Low (J.); P. Coakely (P.); S. Coughlan (Suzie); I. Levi (I.); D. Chemtob (D.); C. Balotta (Claudia); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M.C. Colombo (M.); C. Rossi (Cesare); F. Prati (Francesco); F. Tramuto (F.); F. Vitale (F.); M. Ciccozzi (M.); G. Angarano (Guiseppe); G. Rezza (G.); R. Hemmer (R.); V. Arendt (V.); T. Staub (T.); F. Schneider (F.); F. Roman (Francois); C.A.B. Boucher (Charles); P.H.M. van Bentum (P. H M); K. Brinkman (Kees); E.L.M. Op de Coul (Eline); M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); J. Juttmann (Job); M. Kuipers (M.); N. Langebeek (Nienke); C. Richter (C.); R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. Asjö (Birgitta); V. Ormaasen (Vidar); P. Aavitsland (P.); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo (A.); E. Jablonowska (E.); E. Malolepsza (E.); M. Leszczyszyn-Pynka (M.); W. Szata (W.); A. de Palma (Andre); F. Borges (F.); T. Paix̃ao (T.); V. Duque (V.); F. Aráujo (F.); M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); M. Habekova (M.); M. Mokras (M.); P. Truska (P.); M. Poljak (Mario); D.Z. Babic (Dunja); J. Tomazic (J.); S. Vidmar (Suzanna); P. Karner (P.); C. Gutíerrez (C.); C. deMendoza (C.); I. Erkicia (I.); P. Domingo (P.); X. Camino (X.); M.A. Galindo (Miguel Angel); J.L. Blanco (J.); M. Leal (M.); A. Masabeu (A.); A. Guelar (A.); J.M. Llibre (Josep M.); N. Margall (N.); C. Iribarren (Carlos); S. Gutierrez (S.); J.F. Baldov́i (J.); C.E. Pedreira (Carlos Eduardo); J.M. Gatell (J.); S. Moreno (S.); C. de Mendoza (Carmen); V. Soriano (Virtudes); A. Blaxhult (A.); A. Heidarian (A.); A. Karlsson (A.); K. Aperia-Peipke (K.); I.-M. Bergbrant (I.); M. Gissĺen (M.); M. Svennerholm (M.); P. Bj̈orkman (P.); G. Bratt (G.); M. Carlsson (M.); H. Ekvall (H.); M. Ericsson (M.); M. Ḧofer (M.); B. Johansson (Bert); N. Kuylenstierna (N.); K. Ljungberg (Karl); S. Mäkitalo (S.); A. Strand; K. Öberg (Kjell); T. Berg (Trine)

2012-01-01

textabstractBackground: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory

Automatic detection of lift-off and touch-down of a pick-up walker using 3D kinematics.

Science.gov (United States)

Grootveld, L; Thies, S B; Ogden, D; Howard, D; Kenney, L P J

2014-02-01

Walking aids have been associated with falls and it is believed that incorrect use limits their usefulness. Measures are therefore needed that characterize their stable use and the classification of key events in walking aid movement is the first step in their development. This study presents an automated algorithm for detection of lift-off (LO) and touch-down (TD) events of a pick-up walker. For algorithm design and initial testing, a single user performed trials for which the four individual walker feet lifted off the ground and touched down again in various sequences, and for different amounts of frame loading (Dataset_1). For further validation, ten healthy young subjects walked with the pick-up walker on flat ground (Dataset_2a) and on a narrow beam (Dataset_2b), to challenge balance. One 88-year-old walking frame user was also assessed. Kinematic data were collected with a 3D optoelectronic camera system. The algorithm detected over 93% of events (Dataset_1), and 95% and 92% in Dataset_2a and b, respectively. Of the various LO/TD sequences, those associated with natural progression resulted in up to 100% correctly identified events. For the 88-year-old walking frame user, 96% of LO events and 93% of TD events were detected, demonstrating the potential of the approach. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved.

Ac-loss measurement of coated conductors: The influence of the pick-up coil position

International Nuclear Information System (INIS)

Schmidt, Curt

2008-01-01

The ac-loss measurement by the magnetization method requires calibration for obtaining absolute values. A convenient way of calibration is the calorimetric measurement which yields, within the measuring accuracy, absolute loss values. In the magnetization measurement the hysteresis loop of sample magnetization which determines the losses is measured via the integration of magnetic flux penetrating a pick-up coil. The ratio of flux integral to magnetization integral and hence the calibration factor is however, for a given pick-up coil geometry, not exactly a constant, but depends on the magnetization current pattern within the sample. Especially for thin tapes in perpendicular external field this effect has to be taken into consideration in order to avoid miss measurements. The relation between measured flux and sample magnetization was calculated for special cases of magnetization current distribution in the sample as a function of the pick-up coil position. Furthermore calibration factors were measured as a function of the ac-field amplitude and the result compared with available theoretical models. A good agreement was found between experiment and theory

Picking of foreign television formats by Czech televisions

OpenAIRE

Šopovová, Andrea

2010-01-01

This paper is concerned with one of the impacts of media globalisation and it is a picking of foreign television formats. It analyzes the structure of television programs offered by Czech television broadcasters and its change from 2005 when TV Nova and TV Prima changed their owners to international ones. After the introduction of media globalisation, the paper describes the television formats and then it includes a list of licensed television programs and a comparison of chosen programs with...

Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway

DEFF Research Database (Denmark)

Madsen, Kenneth Lindegaard; Thorsen, Thor Seneca; Rahbek-Clemmensen, Troels

2012-01-01

The scaffolding protein PICK1 (protein interacting with C kinase 1) contains an N-terminal PSD-95/Discs large/ZO-1 (PDZ) domain and a central lipid-binding Bin/amphiphysin/Rvs (BAR) domain. PICK1 is thought to regulate trafficking of its PDZ binding partners but different and even opposing...... functions have been suggested. Here, we apply ELISA-based assays and confocal microscopy in HEK293 cells with inducible PICK1 expression to assess in an isolated system the ability of PICK1 to regulate trafficking of natural and engineered PDZ binding partners. The dopamine transporter (DAT), which...

Cherry Picking Robot Vision Recognition System Based on OpenCV

Directory of Open Access Journals (Sweden)

Zhang Qi Rong

2016-01-01

Full Text Available Through OpenCV function, the cherry in a natural environment image after image preprocessing, color recognition, threshold segmentation, morphological filtering, edge detection, circle Hough transform, you can draw the cherry’s center and circular contour, to carry out the purpose of the machine picking. The system is simple and effective.

Disease: H01449 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available which causes tissue damage. Patients spend a significant amount of time each day picking their skin, that causes psychosocial...for this disease has largely focused on cognitive behavioral therapy and pharmacology. Early psychosocial tr

Periodontal disease and non-communicable diseases. Strength of bidirectional associations

OpenAIRE

Kassier, SM

2016-01-01

Periodontal disease (PD), along with cardiovascular and circulatory disease, diabetes mellitus, chronic respiratory disease and obesity, are globally regarded as some of the major non-communicable diseases (NCDs). The association between PD and these systemic illnesses is described as bidirectional. Gaining an understanding of the strength of the proposed associations between these diseases is important, as it will enable health professionals to identify common risk factors that will allow fo...

Brushes and picks used on nails during the surgical scrub to reduce bacteria: a randomised trial.

Science.gov (United States)

Tanner, J; Khan, D; Walsh, S; Chernova, J; Lamont, S; Laurent, T

2009-03-01

Though brushes are no longer used on the hands and forearms during the surgical scrub, they are still widely used on the nails. The aim of this study was to determine whether nail picks and nail brushes are effective in providing additional decontamination during a surgical hand scrub. A total of 164 operating department staff were randomised to undertake one of the following three surgical hand-scrub protocols: chlorhexidine only; chlorhexidine and a nail pick; or chlorhexidine and a nail brush. Bacterial hand sampling was conducted before and 1h after scrubbing using a modified version of the glove juice method. No statistically significant differences in bacterial numbers were found between any two of the three intervention groups. Nail brushes and nail picks used during surgical hand scrubs do not decrease bacterial numbers and are unnecessary.

The ATLAS beam pick-up based timing system

International Nuclear Information System (INIS)

Ohm, C.; Pauly, T.

2010-01-01

The ATLAS BPTX stations are composed of electrostatic button pick-up detectors, located 175 m away along the beam pipe on both sides of ATLAS. The pick-ups are installed as a part of the LHC beam instrumentation and used by ATLAS for timing purposes. The usage of the BPTX signals in ATLAS is twofold: they are used both in the trigger system and for LHC beam monitoring. The BPTX signals are discriminated with a constant-fraction discriminator to provide a Level-1 trigger when a bunch passes through ATLAS. Furthermore, the BPTX detectors are used by a stand-alone monitoring system for the LHC bunches and timing signals. The BPTX monitoring system measures the phase between collisions and clock with a precision better than 100 ps in order to guarantee a stable phase relationship for optimal signal sampling in the sub-detector front-end electronics. In addition to monitoring this phase, the properties of the individual bunches are measured and the structure of the beams is determined. On September 10, 2008, the first LHC beams reached the ATLAS experiment. During this period with beam, the ATLAS BPTX system was used extensively to time in the read-out of the sub-detectors. In this paper, we present the performance of the BPTX system and its measurements of the first LHC beams.

Influence of uvrB and pKM101 on the spectrum of spontaneous, UV- and gamma-ray-induced base substitutions that revert hisG46 in Salmonella typhimurium

Energy Technology Data Exchange (ETDEWEB)

Eisenstadt, E; Kahng, L -S; Miller, J K; Barnes, W M

1989-01-01

Oligonucleotide probes were used to identify base substitutions in 1089 revertants of hisG46 in Salmonella typhimurium that arose spontaneously or following irradiation with UV- or ..gamma..-rays. The hisG46 allele, carrying a mutant CCC codon (Pro) in place of the wild-type codon CTC (Leu69) reverted via 6 distinguishable mutational events: C to T transitions at codon sites 1 or 2, C to A or C to G transversions at codon site 1, C to A at codon site 2, and an extragenic suppressor mutation. The distribution of hisG46 revertants differed among treatments and was influenced by the DNA-repair capacity of the bacteria. Plasmid pKM101 enhanced the frequencies of both spontaneous adn induced mutations; transversion events were enhanced more efficiently by pKM101 than were transition events. Compared to Uvr/sup +/ bacteria, Uvr/sup -/ bacteria had higher frequencies of spontaneous and induced mutations; transition mutations were enhanced more efficiently than were transversion mutations. The inflence of DNA-repair activiteis on the mutational spectra provides some insights on the origins of spontaneous and UV-induced mutations. (author). 75 refs.; 4 figs.; 4 tabs.

DISEASES: text mining and data integration of disease-gene associations.

Science.gov (United States)

Pletscher-Frankild, Sune; Pallejà, Albert; Tsafou, Kalliopi; Binder, Janos X; Jensen, Lars Juhl

2015-03-01

Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases. The DISEASES resource is accessible through a web interface at http://diseases.jensenlab.org/, where the text-mining software and all associations are also freely available for download. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

DEFF Research Database (Denmark)

Thorsen, Thor S; Madsen, Kenneth L; Rebola, Nelson

2010-01-01

interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal...

Green Grape Detection and Picking-Point Calculation in a Night-Time Natural Environment Using a Charge-Coupled Device (CCD Vision Sensor with Artificial Illumination

Directory of Open Access Journals (Sweden)

Juntao Xiong

2018-03-01

Full Text Available Night-time fruit-picking technology is important to picking robots. This paper proposes a method of night-time detection and picking-point positioning for green grape-picking robots to solve the difficult problem of green grape detection and picking in night-time conditions with artificial lighting systems. Taking a representative green grape named Centennial Seedless as the research object, daytime and night-time grape images were captured by a custom-designed visual system. Detection was conducted employing the following steps: (1 The RGB (red, green and blue. Color model was determined for night-time green grape detection through analysis of color features of grape images under daytime natural light and night-time artificial lighting. The R component of the RGB color model was rotated and the image resolution was compressed; (2 The improved Chan–Vese (C–V level set model and morphological processing method were used to remove the background of the image, leaving out the grape fruit; (3 Based on the character of grape vertical suspension, combining the principle of the minimum circumscribed rectangle of fruit and the Hough straight line detection method, straight-line fitting for the fruit stem was conducted and the picking point was calculated using the stem with an angle of fitting line and vertical line less than 15°. The visual detection experiment results showed that the accuracy of grape fruit detection was 91.67% and the average running time of the proposed algorithm was 0.46 s. The picking-point calculation experiment results showed that the highest accuracy for the picking-point calculation was 92.5%, while the lowest was 80%. The results demonstrate that the proposed method of night-time green grape detection and picking-point calculation can provide technical support to the grape-picking robots.

Bacterial recovery from breast skin of genetically feathered and featherless broiler carcasses immediately following scalding and picking.

Science.gov (United States)

Buhr, R J; Berrang, M E; Cason, J A

2003-10-01

Genetically feathered and featherless sibling broilers selected for matched BW were killed, scalded, and defeathered to determine the consequences of feathers and empty feather follicles on the recovery of bacteria from carcass breast skin. In trial 1, the vents of all carcasses were plugged and sutured before scalding to prevent the expulsion of cloacal contents during picking. In trial 2, half of the carcasses had their vents plugged and sutured. Immediately after defeathering, breast skin was aseptically removed, and bacteria associated with it were enumerated. In trial 1, the levels of bacteria recovered did not differ between feathered and featherless carcasses: Campylobacter log10 1.4 cfu/mL of rinse, coliform log10 1.8, Escherichia coli log10 1.6, and total aerobic bacteria log10 3.1. In trial 2, the carcasses that had vents plugged and sutured had lower levels of all four types of bacteria (differences of Campylobacter log10 0.7 cfu/mL, coliform log10 1.8, E. coli log10 1.7, and total aerobic bacteria log10 0.5) than those carcasses with open vents. The lower levels of bacteria recovered from carcasses with the vents plugged and sutured during picking enabled detection of small but significant differences between feathered and featherless carcasses. The level of coliform and E. coli recovered was slightly higher by log10 0.7 cfu for feathered carcasses, but featherless carcasses had marginally higher levels of total aerobic bacteria by log10 0.4 cfu. Feathered and featherless carcasses with open vents during picking did not differ in the levels of recovery of coliform, E. coli, and total aerobic bacteria from breast skin.

Cannabis-associated arterial disease.

Science.gov (United States)

Desbois, Anne Claire; Cacoub, Patrice

2013-10-01

The aim of this study was to describe the different arterial complications reported in cannabis smokers. This study was a literature review. Cannabis use was found to be associated with stroke, myocardial infarction, and lower limb arteritis. Arterial disease involved especially young men. There was a very strong temporal link between arterial complications and cannabis use for stroke and myocardial infarction episodes. Patient outcome was closely correlated with cannabis withdrawal and relapses associated with cannabis rechallenge. Cannabis use was associated with particular characteristics of arterial disease. The increased risk of myocardial infarction onset occurred within 1 hour of smoking marijuana compared with periods of non-use. Strokes occurred mainly in the posterior cerebral circulation. Compared with cohorts of thromboangiitis obliterans patients, those with cannabis-associated limb arteritis were younger, more often male, and had more frequent unilateral involvement of the lower limbs at clinical presentation. Cannabis use is associated with arterial disease such as stroke, myocardial infarction, and limbs arteritis. It appears essential to investigate cannabis use in young patients presenting with such arterial manifestations, as outcome is closely correlated with cannabis withdrawal. Copyright © 2013 Elsevier Inc. All rights reserved.

El Club Dumas de Arturo Pérez-Reverte como paradigma de la narrativa posmoderna española

OpenAIRE

Isaac Gómez Laguna

2015-01-01

El presente artículo ofrece un análisis de los diferentes rasgos posmodernistas que aparecen de manera explícita en El Club Dumas, novela insignia de la narrativa posmoderna en España, en torno a tres ejes centrales: a) género de la obra e intertextualidad, b) indeterminación e irrealidad, y c) individuo y sociedad. Mediante esta reflexión pretendemos evidenciar que su autor, Arturo Pérez-Reverte, no solo crea una novela puramente posmoderna, sino que su obra le sirve para teorizar acerca del...

Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.

Science.gov (United States)

Tukachinsky, Hanna; Kuzmickas, Ryan P; Jao, Cindy Y; Liu, Jing; Salic, Adrian

2012-08-30

The Hedgehog (Hh) signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp) and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Comparative analysis of acid sphingomyelinase distribution in the CNS of rats and mice following intracerebroventricular delivery.

Directory of Open Access Journals (Sweden)

Christopher M Treleaven

Full Text Available Niemann-Pick A (NPA disease is a lysosomal storage disorder (LSD caused by a deficiency in acid sphingomyelinase (ASM activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO mice could be partially alleviated by intracerebroventricular (ICV infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.

Two-line hybrid rice male sterile line 'NHR111S' with a marker of green-revertible albino leaves

International Nuclear Information System (INIS)

Wu Wei; Liu Xin; Shu Xiaoli; Shu Qingyao; Xia Yingwu; Wu Dianxing

2006-01-01

NHR111S is a new two-line male sterile line with a marker of green-revertible albino leave that was bred from in vitro mutagens is of the thermo/photoperiod-sensitive male sterile line 'Guangzhan63S' by 60 Co γ-rays. It has the same desired agronomic traits, fertility characteristics and combining ability as characteristics of the parent. It is convenient to develop leaf color marker-aided elimination strategy in the multiplication and production of hybrid rice seeds. (authors)

Skin picking disorder with co-occurring body dysmorphic disorder

DEFF Research Database (Denmark)

Grant, Jon E; Redden, Sarah A; Leppink, Eric W

2015-01-01

There is clinical overlap between skin picking disorder (SPD) and body dysmorphic disorder (BDD), but little research has examined clinical and cognitive correlates of the two disorders when they co-occur. Of 55 participants with SPD recruited for a neurocognitive study and two pharmacological st...... unique clinical and cognitive aspects of SPD may be more pronounced. Future work should explore possible subgroups in SPD and whether these predict different treatment outcomes....

Nanorobotic Manipulation Setup for Pick-and-Place Handling and non-destructive Characterization of Carbon Nanotubes

DEFF Research Database (Denmark)

Eicchorn, V.; Carlson, Kenneth; Andersen, Karin Nordström

2007-01-01

. The pick-and-place task is carried out by using an electrothermal actuated microgripper, designed for controlled manipulation of nanotubes. The nanotube is picked up from an array of multiwalled carbon nanotubes (MWCNTs) and transferred to the tip of an atomic force microscope (AFM) probe in order...... to assemble a high-aspect ratio AFM supertip. Another application of the nanorobotic setup considered in this paper is the nondestructive mechanical characterization of CNTs. A piezoresistive AFM probe is used to bend MWCNTs, while the bending force is measured, in order to estimate the Young's modulus...

Sodium Pick-Up Ion Observations in the Solar Wind Upstream of Mercury

Science.gov (United States)

Jasinski, J. M.; Raines, J. M.; Slavin, J. A.; Regoli, L. R.; Murphy, N.

2018-05-01

We present the first observations of sodium pick-up ions upstream of Mercury’s magnetosphere. From these observations we infer properties of Mercury’s sodium exosphere and implications for the solar wind interaction with Mercury’s magnetosphere.

Seasonal variation of Martian pick-up ions: Evidence of breathing exosphere

Science.gov (United States)

Yamauchi, M.; Hara, T.; Lundin, R.; Dubinin, E.; Fedorov, A.; Sauvaud, J.-A.; Frahm, R. A.; Ramstad, R.; Futaana, Y.; Holmstrom, M.; Barabash, S.

2015-12-01

The Mars Express (MEX) Ion Mass Analyser (IMA) found that the detection rate of the ring-like distribution of protons in the solar wind outside of the bow shock to be quite different between Mars orbital summer (around perihelion) and orbital winter (around aphelion) for four Martian years, while the north-south asymmetry is much smaller than the perihelion-aphelion difference. Further analyses using eight years of MEX/IMA solar wind data between 2005 and 2012 has revealed that the detection frequency of the pick-up ions originating from newly ionized exospheric hydrogen with certain flux strongly correlates with the Sun-Mars distance, which changes approximately every two years. Variation due to the solar cycle phase is not distinguishable partly because this effect is masked by the seasonal variation under the MEX capability of plasma measurements. This finding indicates that the variation in solar UV has a major effect on the formation of the pick-up ions, but this is not the only controlling factor.

Testbeam Studies on Pick-Up in Sensors with Embedded Pitch Adapters

CERN Document Server

Rehnisch, Laura; The ATLAS collaboration

2018-01-01

Embedded pitch adapters are an alternative solution to external pitch adapters widely used to facilitate the wire-bonding step when connecting silicon strip sensors and readout electronics of different pitch. The pad-pitch adaption can be moved into the sensor fabrication step by implementing a second layer of metal tracks, connected by vias to the primary metal layer of sensor strips. Such a solution, however, might bear the risk of performance losses introduced by various phenomena. One of these effects, the undesired capacitive coupling between the silicon bulk and this second metal layer (pick-up) has been investigated in photon testbeam measurements. For a worst-case embedded pitch adapter design, expected to be maximally susceptible to pick-up, a qualitative analysis has visualized the effect as a function of the location on the second metal layer structure. It was further found that the unwanted effect decreases towards expected values for operating thresholds of the binary readout used. Suggestions fo...

Automatic first-arrival picking based on extended super-virtual interferometry with quality control procedure

Science.gov (United States)

An, Shengpei; Hu, Tianyue; Liu, Yimou; Peng, Gengxin; Liang, Xianghao

2017-12-01

Static correction is a crucial step of seismic data processing for onshore play, which frequently has a complex near-surface condition. The effectiveness of the static correction depends on an accurate determination of first-arrival traveltimes. However, it is difficult to accurately auto-pick the first arrivals for data with low signal-to-noise ratios (SNR), especially for those measured in the area of the complex near-surface. The technique of the super-virtual interferometry (SVI) has the potential to enhance the SNR of first arrivals. In this paper, we develop the extended SVI with (1) the application of the reverse correlation to improve the capability of SNR enhancement at near-offset, and (2) the usage of the multi-domain method to partially overcome the limitation of current method, given insufficient available source-receiver combinations. Compared to the standard SVI, the SNR enhancement of the extended SVI can be up to 40%. In addition, we propose a quality control procedure, which is based on the statistical characteristics of multichannel recordings of first arrivals. It can auto-correct the mispicks, which might be spurious events generated by the SVI. This procedure is very robust, highly automatic and it can accommodate large data in batches. Finally, we develop one automatic first-arrival picking method to combine the extended SVI and the quality control procedure. Both the synthetic and the field data examples demonstrate that the proposed method is able to accurately auto-pick first arrivals in seismic traces with low SNR. The quality of the stacked seismic sections obtained from this method is much better than those obtained from an auto-picking method, which is commonly employed by the commercial software.

An agent-based approach with collaboration among agents. Estimation of wholesale electricity price on PJM and artificial data generated by a mean reverting model

International Nuclear Information System (INIS)

Sueyoshi, Toshiyuki

2010-01-01

This study examines the performance of MAIS (Multi-Agent Intelligent Simulator) equipped with various learning capabilities. In addition to the learning capabilities, the proposed MAIS incorporates collaboration among agents. The proposed MAIS is applied to estimate a dynamic change of wholesale electricity price in PJM (Pennsylvania-New Jersey-Mainland) and an artificial data set generated by a mean reverting model. Using such different types of data sets, the methodological validity of MAIS is confirmed by comparing it with other well-known alternatives in computer science. This study finds that the MAIS needs to incorporate both the mean reverting model and the collaboration behavior among agents in order to enhance its estimation capability. The MAIS discussed in this study will provide research on energy economics with a new numerical capability that can investigate a dynamic change of not only wholesale electricity price but also speculation and learning process of traders. (author)

Addison's disease and its associations

OpenAIRE

Puttanna, Amar; Cunningham, Alana Rosaleen; Dainty, Philip

2013-01-01

Addison's disease is a relatively rare endocrine condition resulting from adrenal insufficiency due to various causes. Weight loss is a common feature; however, patients may be seen by a variety of specialists, even requiring acute admission before the diagnosis is made. Addison's disease is commonly associated with other autoimmune diseases. In some cases such as autoimmune polyendocrine syndromes (APS) types 1 and 2, these associations are more commonly found. We present a case of one such ...

Serine 77 in the PDZ domain of PICK1 is a protein kinase Cα phosphorylation site regulated by lipid membrane binding

DEFF Research Database (Denmark)

Ammendrup-Johnsen, Ina; Thorsen, Thor Seneca; Gether, Ulrik

2012-01-01

PICK1 (protein interacting with C kinase 1) contains an N-terminal protein binding PDZ domain and a C-terminal lipid binding BAR domain. PICK1 plays a key role in several physiological processes, including synaptic plasticity. However, little is known about the cellular mechanisms governing the a...... lipid binding and/or polymerization capacity. We propose that PICK1 is phosphorylated at Ser77 by PKCα preferentially when bound to membrane vesicles and that this phosphorylation in turn modulates its cellular distribution....

Determining The Optimal Order Picking Batch Size In Single Aisle Warehouses

NARCIS (Netherlands)

T. Le-Duc (Tho); M.B.M. de Koster (René)

2002-01-01

textabstractThis work aims at investigating the influence of picking batch size to average time in system of orders in a one-aisle warehouse under the assumption that order arrivals follow a Poisson process and items are uniformly distributed over the aisle's length. We model this problem as an

Analysis of action of device with spring pins for picking up of retted flax straw

Directory of Open Access Journals (Sweden)

V. G. Chernikov

2016-01-01

Full Text Available Weather conditions in flax cultivation areas during harvesting time can be characterized with high rainfalls, relative humidity and, in some areas, extremely low temperature. Clogging of fields with stones, grass germination through flax swaths, often an absence of homogeneity on length and thickness of straw in swaths require working out new devices for straw lifting. Existing devices for picking up do not provide a high-quality lifting of flax swaths and have a low coefficient of reliability of the process. Researches and experimental-design works were carried out to create a constructive-technological scheme of the picking up device of cylindrical type with spring-loaded rigid pins. The mathematical model of the device operation when a pin touching an obstacle. The condition of balance of the mechanism under which the pin of a cilinder will operate technological process of picking up of retted flax straw without action of the safety device (spring was described. The offered method of calculation of operation of this device was introduced in a common flax swath lifter-turners

Prediction of disease and phenotype associations from genome-wide association studies.

Directory of Open Access Journals (Sweden)

Stephanie N Lewis

Full Text Available Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases.Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits.The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

“Pick-up Lines”: A Fun Way to Facilitate Learning Microbiological Concepts

Directory of Open Access Journals (Sweden)

Thomas Edison E. dela Cruz

2014-05-01

Full Text Available Learning microbiology can be made fun by writing funny lines related to microbiology. Students were tasked to create their own pick-up lines and explain these based on their understanding of the basic concepts in microbiology.

Understanding Human Hand Gestures for Learning Robot Pick-and-Place Tasks

Directory of Open Access Journals (Sweden)

Hsien-I Lin

2015-05-01

Full Text Available Programming robots by human demonstration is an intuitive approach, especially by gestures. Because robot pick-and-place tasks are widely used in industrial factories, this paper proposes a framework to learn robot pick-and-place tasks by understanding human hand gestures. The proposed framework is composed of the module of gesture recognition and the module of robot behaviour control. For the module of gesture recognition, transport empty (TE, transport loaded (TL, grasp (G, and release (RL from Gilbreth's therbligs are the hand gestures to be recognized. A convolution neural network (CNN is adopted to recognize these gestures from a camera image. To achieve the robust performance, the skin model by a Gaussian mixture model (GMM is used to filter out non-skin colours of an image, and the calibration of position and orientation is applied to obtain the neutral hand pose before the training and testing of the CNN. For the module of robot behaviour control, the corresponding robot motion primitives to TE, TL, G, and RL, respectively, are implemented in the robot. To manage the primitives in the robot system, a behaviour-based programming platform based on the Extensible Agent Behavior Specification Language (XABSL is adopted. Because the XABSL provides the flexibility and re-usability of the robot primitives, the hand motion sequence from the module of gesture recognition can be easily used in the XABSL programming platform to implement the robot pick-and-place tasks. The experimental evaluation of seven subjects performing seven hand gestures showed that the average recognition rate was 95.96%. Moreover, by the XABSL programming platform, the experiment showed the cube-stacking task was easily programmed by human demonstration.

Addison's disease and its associations.

Science.gov (United States)

Puttanna, Amar; Cunningham, Alana Rosaleen; Dainty, Philip

2013-07-26

Addison's disease is a relatively rare endocrine condition resulting from adrenal insufficiency due to various causes. Weight loss is a common feature; however, patients may be seen by a variety of specialists, even requiring acute admission before the diagnosis is made. Addison's disease is commonly associated with other autoimmune diseases. In some cases such as autoimmune polyendocrine syndromes (APS) types 1 and 2, these associations are more commonly found. We present a case of one such patient who presented to the acute medical team having been referred to the gastrointestinal services in the previous year for persistent vomiting and weight loss. On review of history, the cause of vomiting and weight loss was questioned and combined with subsequent biochemical testing a diagnosis of Addison's disease was made. The patient was also noted to have other associated endocrine and autoimmune conditions.

Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

Science.gov (United States)

Adnan, Humaira; Zhang, Zhenbo; Park, Hyun-Joo; Tailor, Chetankumar; Che, Clare; Kamani, Mustafa; Spitalny, George; Binnington, Beth; Lingwood, Clifford

2016-01-01

Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon), to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin) containing genetically inactivated (± an N-terminal polyleucine tail) A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF) mutant (5-10x), F508delCFTR Golgi maturation (glucocerobrosidase (GCC) in N370SGCC Gaucher Disease fibroblasts (3x), another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases.

Automatic picking of the first arrival event using the unwrapped-phase of the Fourier transformed wavefield

KAUST Repository

Choi, Yun Seok

2011-01-01

First-arrival picking has long suffered from cycle skipping, especially when the first arrival is contaminated with noise or have experienced complex near surface phenomena. We propose a new algorithm for automatic picking of first arrivals using an approach based on unwrapping the phase. We unwrap the phase by taking the derivative of the Fourier-transformed wavefield with respect to the angular frequency and isolate its amplitude component. To do so, we first apply a damping function to the seismic trace, calculate the derivative of the wavefield with respect to the angular frequency, divide the derivative of wavefield by the wavefield itself, and finally take its imaginary part. We compare our derivative approach to the logarithmic one and show that the derivative approach does not suffer from the phase wrapping or cycle-skipping effects. Numerical examples show that our automatic picking algorithm gives convergent and reliable results for the noise-free synthetic data and noisy field data. © 2011 Society of Exploration Geophysicists.

Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies.

Science.gov (United States)

Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L; Bale, Shridhar; Flyak, Andrew I; Crowe, James E; Chandran, Kartik; Saphire, Erica Ollmann

2016-02-23

The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. Ebola virus uses its glycoprotein (GP) to enter new host cells. During entry, GP must be cleaved by human enzymes in order for receptor binding to occur. Here, we provide the crystal structure of the cleaved form of Ebola virus GP. We demonstrate that cleavage exposes a site at the top of GP and that this site binds the critical domain C of the receptor, termed Niemann-Pick C1 (NPC1). We perform mutagenesis to find parts of the site essential for binding NPC1 and map distinct roles for an upper, charged crest and lower, hydrophobic trough in cleaved GP. We find that this 3-dimensional site is conserved across the filovirus family and that antibody directed against this site is able to bind cleaved GP from every filovirus tested and neutralize viruses bearing those GPs. Copyright © 2016 Bornholdt et al.

An automated framework for NMR resonance assignment through simultaneous slice picking and spin system forming

KAUST Repository

Abbas, Ahmed

2014-04-19

Despite significant advances in automated nuclear magnetic resonance-based protein structure determination, the high numbers of false positives and false negatives among the peaks selected by fully automated methods remain a problem. These false positives and negatives impair the performance of resonance assignment methods. One of the main reasons for this problem is that the computational research community often considers peak picking and resonance assignment to be two separate problems, whereas spectroscopists use expert knowledge to pick peaks and assign their resonances at the same time. We propose a novel framework that simultaneously conducts slice picking and spin system forming, an essential step in resonance assignment. Our framework then employs a genetic algorithm, directed by both connectivity information and amino acid typing information from the spin systems, to assign the spin systems to residues. The inputs to our framework can be as few as two commonly used spectra, i.e., CBCA(CO)NH and HNCACB. Different from the existing peak picking and resonance assignment methods that treat peaks as the units, our method is based on \\'slices\\', which are one-dimensional vectors in three-dimensional spectra that correspond to certain (N, H) values. Experimental results on both benchmark simulated data sets and four real protein data sets demonstrate that our method significantly outperforms the state-of-the-art methods while using a less number of spectra than those methods. Our method is freely available at http://sfb.kaust.edu.sa/Pages/Software.aspx. © 2014 Springer Science+Business Media.

Communicable diseases associated with water

International Nuclear Information System (INIS)

Dil, A.S.

1997-01-01

The diseases associated with contaminated water remain among the most serious public health problems for much of the world's population living in developing countries. Most of the disease agents that contaminated water and food are biological and come from animal or human faeces. They include bacteria, viruses, protozoa and helminths and multiply in the alimentary tract and are excreted with the faeces. Without proper sanitation they find their way into other water bodies from where they can infect other people. Most of the diseases associated with water are communicable. According to Bradley the diseases associated with water can be classified in four categories: waterborne water-washed, water-based and water related and a fifth category emerging in developed countries could be called water-dispersed. The experiences of these diseases in various in various parts of Pakistan and the role played by National Institute of Health (NIH) in investigation will be discussed: some of them being hepatitis E epidemic in Islamabad (1993,94,95), experience at Nawabshah and some others will be discussed in detail along with their preventive and control measures. (author)

Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect.

Science.gov (United States)

Filho, Paulo Ricardo Marques; Vercelino, Rafael; Cioato, Stefania Giotti; Medeiros, Liciane Fernandes; de Oliveira, Carla; Scarabelot, Vanessa Leal; Souza, Andressa; Rozisky, Joanna Ripoll; Quevedo, Alexandre da Silva; Adachi, Lauren Naomi Spezia; Sanches, Paulo Roberto S; Fregni, Felipe; Caumo, Wolnei; Torres, Iraci L S

2016-01-04

Neuropathic pain (NP) is a chronic pain modality that usually results of damage in the somatosensory system. NP often shows insufficient response to classic analgesics and remains a challenge to medical treatment. The transcranial direct current stimulation (tDCS) is a non-invasive technique, which induces neuroplastic changes in central nervous system of animals and humans. The brain derived neurotrophic factor plays an important role in synaptic plasticity process. Behavior changes such as decreased locomotor and exploratory activities and anxiety disorders are common comorbidities associated with NP. Evaluate the effect of tDCS treatment on locomotor and exploratory activities, and anxiety-like behavior, and peripheral and central BDNF levels in rats submitted to neuropathic pain model. Rats were randomly divided: Ss, SsS, SsT, NP, NpS, and NpT. The neuropathic pain model was induced by partial sciatic nerve compression at 14 days after surgery; the tDCS treatment was initiated. The animals of treated groups were subjected to a 20 minute session of tDCS, for eight days. The Open Field and Elevated Pluz Maze tests were applied 24 h (phase I) and 7 days (phase II) after the end of tDCS treatment. The serum, spinal cord, brainstem and cerebral cortex BDNF levels were determined 48 h (phase I) and 8 days (phase II) after tDCS treatment by ELISA. The chronic constriction injury (CCI) induces decrease in locomotor and exploratory activities, increases in the behavior-like anxiety, and increases in the brainstem BDNF levels, the last, in phase II (one-way ANOVA/SNK, PtDCS treatment already reverted all these effects induced by CCI (one-way ANOVA/SNK, PtDCS treatment decreased serum and cerebral cortex BDNF levels and it increased these levels in the spinal cord in phase II (one-way ANOVA/SNK, PtDCS reverts behavioral alterations associated to neuropathic pain, indicating possible analgesic and anxiolytic tDCS effects. tDCS treatment induces changes in the BDNF levels

Genetic variations of the NPC1L1 gene associated with hepatitis C virus (HCV) infection and biochemical characteristics of HCV patients in China.

Science.gov (United States)

Zhang, A-Mei; Zhang, Cheng-Lin; Song, Yuzhu; Zhao, Ping; Feng, Yue; Wang, Binghui; Li, Zheng; Liu, Li; Xia, Xueshan

2016-12-01

About 2% of the world population is infected with hepatitis C virus (HCV), a leading cause of hepatic cirrhosis and hepatocellular carcinoma. The Niemann-Pick C1-like 1 cholesterol absorption receptor (NPC1L1) was recently identified to be an important factor for HCV entry into host cells. Whether genetic variations of the NPC1L1 gene are associated with HCV infection is unknown. In this study, five single nucleotide polymorphisms (SNPs) of the NPC1L1 gene were analyzed in 261 HCV-infected individuals and 265 general controls from Yunnan Province, China. No significant differences were identified in genotypes or alleles of the SNPs between the two groups. After constructing haplotypes based on the five SNPs, a significant difference between HCV-infected individuals and general controls was shown for two haplotypes. Haplotype GCCTT appeared to be a protective factor and haplotype GCCCT was a risk factor for HCV-infected individuals. Genotypes of four SNPs correlated with biochemical characteristics of HCV-infected persons. Genotypes of SNPs rs799444 and rs2070607 were correlated with total bilirubin. Genotype TT of rs917098 was a risk factor for the gamma-glutamyltransferase level. Furthermore, HCV-infected individuals carrying genotype GG of rs41279633 showed statistically higher gamma-glutamyltransferase levels than HCV-infected persons with GT and TT. The results of this study identified the association between genetic susceptibility of the NPC1L1 gene and HCV infection, as well as biochemical characteristics of HCV-infected persons in Yunnan, China. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

El Club Dumas de Arturo Pérez-Reverte como paradigma de la narrativa posmoderna española

Directory of Open Access Journals (Sweden)

Isaac Gómez Laguna

2015-06-01

Full Text Available El presente artículo ofrece un análisis de los diferentes rasgos posmodernistas que aparecen de manera explícita en El Club Dumas, novela insignia de la narrativa posmoderna en España, en torno a tres ejes centrales: a género de la obra e intertextualidad, b indeterminación e irrealidad, y c individuo y sociedad. Mediante esta reflexión pretendemos evidenciar que su autor, Arturo Pérez-Reverte, no solo crea una novela puramente posmoderna, sino que su obra le sirve para teorizar acerca del posmodernismo.

The Quality of Rambak Cracker from Rabbit Skin (Water Content and Swelling Power using The Different Technique of Fur Picking

Directory of Open Access Journals (Sweden)

Dedes Amertaningtyas

2014-11-01

Full Text Available This objective of this researchwas to compare the different technique of fur picking (liming and boiling inthe quality rambak cracker from rabbit skin on water content and swelling power.Materials of this research were 20 drying rabbit skin 5 – 6 months old. The tTest was using to compare the different technique of fur picking. Theindependent variables of this research were water content and swelling power onrambak cracker from rabbit skin. The result showed that the different techniqueof fur picking had highly significant effect (P<0.01 on water content and  expanding rate. The best result was limingtechnique of fur picking. It had the following properties: Water content of 1.5922% and expending rate of 855.3798 %. The conclusion showed that the use limingof 4% produced high quality of rambak cracker from rabbit skin or anotheranimal skin (cow, buffalo, chicken or fish. Keywords: rambak cracker, rabbit skin, water content,expanding rate

Perbandingan Algoritma Simulated Annealing dan Harmony Search dalam Penerapan Picking Order Sequence

Directory of Open Access Journals (Sweden)

Tanti Octavia

2017-12-01

Full Text Available Implementation of mobile rack warehouse is commonly used in manufacturing industry because it can minimize the warehouse area used. Applying picking orders in taking of Stock Keeping Unit (SKU on mobile rack warehouses could give fast loading order. This research aims to find out which algorithm is better in applying picking order sequence in mobile rack warehouse. The algorithm used is Simualted Annealing (SA and Harmony Search (HS algorithm. Both of these algorithms will be compared in terms of the gap with the shortest path method.The result shows that the HS algorithm produces a better solution than the SA algorithm with lower CPU time, but the convergence rate of HS is lower than that of SA.HS was able to produce a better solution than the shortest path method of 9 cases, while SA only 8 cases from 15 cases.

Pick up screens for x-ray image intensifier tubes employing evaporated activated scintillator layer

International Nuclear Information System (INIS)

Spicer, W.E.

1976-01-01

The present invention relates in general to methods for making pick-up screens for x-ray image intensifier tubes and, more particularly, to an improved method wherein the x-ray fluorescent phosphor screen element is formed by evaporation of an alkali metal halide material in vacuum and condensing the evaporated material on an x-ray transparent portion of the x-ray intensifier tube, whereby a curved x-ray image pick-up screen is formed which has improved quantum efficiency and resolution. Such improved x-ray image intensifier tubes are especially useful for, but not limited in use to x-ray systems and for intensifying gamma ray images obtained in applications of nuclear medicine. 7 claims, 5 drawing figures

Exome localization of complex disease association signals

Directory of Open Access Journals (Sweden)

Lewis Cathryn M

2011-02-01

Full Text Available Abstract Background Genome-wide association studies (GWAS of common diseases have had a tremendous impact on genetic research over the last five years; the field is now moving from microarray-based technology towards next-generation sequencing. To evaluate the potential of association studies for complex diseases based on exome sequencing we analysed the distribution of association signal with respect to protein-coding genes based on GWAS data for seven diseases from the Wellcome Trust Case Control Consortium. Results We find significant concentration of association signal in exons and genes for Crohn's Disease, Type 1 Diabetes and Bipolar Disorder, but also observe enrichment from up to 40 kilobases upstream to 40 kilobases downstream of protein-coding genes for Crohn's Disease and Type 1 Diabetes; the exact extent of the distribution is disease dependent. Conclusions Our work suggests that exome sequencing may be a feasible approach to find genetic variation associated with complex disease. Extending the exome sequencing to include flanking regions therefore promises further improvement of covering disease-relevant variants.

A comparative study on fluorescent cholesterol analogs as versatile cellular reporters

DEFF Research Database (Denmark)

Sezgin, Erdinc; Betul Can, Fatma; Schneider, Falk

2016-01-01

Cholesterol is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of cholesterol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently...... for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase separated giant unilamellar vesicles (GUVs) and giant plasma membrane vesicles (GPMVs); 2) cellular trafficking, specifically subcellular localization in Niemann-Pick C...... in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent cholesterol analogs in visualizing cellular cholesterol dynamics....

Interstitial lung disease associated with connective tissue diseases

International Nuclear Information System (INIS)

Medina, Yimy F; Restrepo, Jose Felix; Iglesias, Antonio; Ojeda, Paulina; Matiz, Carlos

2007-01-01

An interstitial lung disease (ILD) belongs to a group of diffuse parenchyma lung diseases it should be differentiated from other pathologies among those are idiopathic and ILD associated to connective tissue diseases (CTD) New concepts have been developed in the last years and they have been classified in seven defined subgroups. It has been described the association of each one of these subgroups with CTD. Natural history and other aspects of its treatment is not known completely .For complete diagnose it is required clinical, image and histopathologic approaches. The biopsy lung plays an essential role. It is important to promote and to stimulate the subclasification of each subgroup with the purpose of knowing their natural history directing the treatment and to improve their outcome

Analysis of the Impact of Storage Parameters and the Size of Orders on the Choice of the Method for Routing Order Picking

Directory of Open Access Journals (Sweden)

Grzegorz Tarczyński

2012-01-01

Full Text Available The paper presents an analysis of the impact of the number of picking aisles, slots in a rack, the size of pick lists, and the routing method on the performance of the order picking process. In the analysis, the forklift truck's maneuvers such as turns back and turns aside, omitted by some scientists, are considered. Although only random storage assignment is examined in this paper, the possible congestion effect is considered. Experiments were performed by the use of simulations. (original abstract

Laparoscopic ovum pick-up in spotted paca ( Cuniculus pacas )

OpenAIRE

Barros,F.F.P.C.; Teixeira,P.P.M.; Uscategui,R.A.R.; Coutinho,L.N.; Brito,M.B.S.; Kawanami,A.E.; Almeida,V.T.; Mariano,R.S.G.; Nociti,R.P.; Machado,M.R.F.; Vicente,W.R.R.

2016-01-01

ABSTRACT The aim of this work is study the laparoscopic ovum pick-up (LapOPU) technique in spotted paca, describing surgery details, complications and oocyte recovery rate. Nine healthy adult non-pregnant captive females were used, in a total of 39 procedures. When the surgical plane of anaesthesia was achieved, the females were positioned at 20º Trendelenburg. Three 6mm trocars were placed on right and left inguinal and hypogastric regions. Abdomen was inflated with CO2 and the intra-abdomin...

The pick-up mechanism in composite particle emission processes

International Nuclear Information System (INIS)

Zhang Jingshang; Yan Shiwei; Wang Cuilan

1992-01-01

The pick-up mechanism has been included in the exciton model for the light composite particle emissions. Based on the cluster phase space integration method the formation probabilities of α,d,t, 3 He are obtained. The calculation results of (n,t) cross sections indicate that this theoretical method can reproduce the experimental data nicely. For triton emissions in pre-equilibrium reaction processes, the semi-direct reactions are the dominant terms which are just omitted in the previous model calculation

Membrane localization is critical for activation of the PICK1 BAR domain

DEFF Research Database (Denmark)

Madsen, Kenneth L; Eriksen, Jacob; Milan-Lobo, Laura

2008-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood....

An improved contour symmetry axes extraction algorithm and its application in the location of picking points of apples

Energy Technology Data Exchange (ETDEWEB)

Wang, D.; Song, H.; Yu, X.; Zhang, W.; Qu, W.; Xu, Y.

2015-07-01

The key problem for picking robots is to locate the picking points of fruit. A method based on the moment of inertia and symmetry of apples is proposed in this paper to locate the picking points of apples. Image pre-processing procedures, which are crucial to improving the accuracy of the location, were carried out to remove noise and smooth the edges of apples. The moment of inertia method has the disadvantage of high computational complexity, which should be solved, so convex hull was used to improve this problem. To verify the validity of this algorithm, a test was conducted using four types of apple images containing 107 apple targets. These images were single and unblocked apple images, single and blocked apple images, images containing adjacent apples, and apples in panoramas. The root mean square error values of these four types of apple images were 6.3, 15.0, 21.6 and 18.4, respectively, and the average location errors were 4.9°, 10.2°, 16.3° and 13.8°, respectively. Furthermore, the improved algorithm was effective in terms of average runtime, with 3.7 ms and 9.2 ms for single and unblocked and single and blocked apple images, respectively. For the other two types of apple images, the runtime was determined by the number of apples and blocked apples contained in the images. The results showed that the improved algorithm could extract symmetry axes and locate the picking points of apples more efficiently. In conclusion, the improved algorithm is feasible for extracting symmetry axes and locating the picking points of apples. (Author)

Preliminary Specifications for the PS Pick-ups Amplifier to be used in the Transverse Damping System

CERN Document Server

Belleman, J; CERN. Geneva. AB Department

2003-01-01

The pick-up amplification stage to be used for the CODD in the PS is presently under redesign. It appears that the constraints for the circuit are very similar to those of the transverse feedback project. The AB/BDI group and in particular its PI section has kindly agreed to fulfil the RF group constraints so as to obtain a common design with a common control interface. The reliability aspect is not treated here. Nevertheless radiation has been considered. At the locations foreseen for the pick-ups (SS 2, 94, 98), the annual dose measured on the vacuum chamber (ref: CERN-TIS-2002-06-TE) is about 1000 Gray per year. This value is to be compared to the 100 Gy considered as the critical dose for electronic circuits. The radiation problem has been solved for the CODD pick-ups using distance and shield (active circuits 2 meters below the floor composed of concrete slabs). The same lay out will be applied for the dampers with the drawback of the capacitive plates being loaded with a low impedance -5 meters long- ca...

Normative values and the effects of age, gender, and handedness on the Moberg Pick-Up Test.

Science.gov (United States)

Amirjani, Nasim; Ashworth, Nigel L; Gordon, Tessa; Edwards, David C; Chan, K Ming

2007-06-01

The Moberg Pick-Up Test is a standardized test for assessing hand dexterity. Although reduction of sensation in the hand occurs with aging, the effect of age on a subject's performance of the Moberg Pick-Up Test has not been examined. The primary goal of this study was to examine the impact of aging and, secondarily, the impact of gender and handedness, on performance of the Moberg Pick-Up Test in 116 healthy subjects. The average time to complete each of the four subsets of the test was analyzed using the Kruskal-Wallis, Mann-Whitney U, and Wilcoxon signed-rank tests. The results show that hand dexterity of the subjects was significantly affected by age, with young subjects being the fastest and elderly subjects the slowest. Women accomplished the test faster than men, and task performance with the dominant hand was faster than with the non-dominant hand. Use of normative values established based on age and gender is a valuable objective tool to gauge hand function in patients with different neurologic disorders.

Efficient data analysis and travel time picking methods for crosshole GPR experiments

DEFF Research Database (Denmark)

Keskinen, Johanna; Moreau, Julien; Nielsen, Lars

2013-01-01

to the source position, and the vertical axis to the travel time. Using OpendTect (dGB Earth Sciences), this data cube is then displayed and inspected in a 3D environment, which allows for effective and efficient data analysis. Quality control and data editing of the individual transmitter gathers can be rapidly......-attribute analyses. We believe that this approach to 3D representation and analysis of GPR crosshole data greatly improves consistency in travel time picking and reduces the time needed for the picking process. Moreover, the approach is well suited for generation of high quality input data for tomographic inversion...... methods. Future time-lapse GPR studies of different types of chalk aim at characterizing the flow characteristics of these economically important lithologies. In the framework of the current study, we have collected new crosshole GPR data from a site located in a former quarry in Eastern Denmark, where...

Cometary pick-up ions observed near Giacobini-Zinner

Science.gov (United States)

Gloeckler, G.; Hovestadt, D.; Ipavich, F. M.; Scholer, M.; Klecker, B.

1986-01-01

The number and energy density of cometary water-group ions observed near Comet Giacobini-Zinner are derived using the rest-frame distribution functions. The data reveal that density profiles of inbound and outbound passes and their shape correlate with pick-up ion production model predictions. The lose rate and production rate of water-group cometary molecules calculated from predicted and measured density profiles are 2 x 10 to the -6th/sec and 2.6 x 10 to the 28th/sec respectively. The shapes of the distribution functions are examined to study the solar wind/cometary ions interaction process.

Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

Directory of Open Access Journals (Sweden)

Humaira Adnan

Full Text Available Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD, to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon, to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin containing genetically inactivated (± an N-terminal polyleucine tail A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF mutant (5-10x, F508delCFTR Golgi maturation (<10x, cell surface expression (20x and chloride transport (2x in F508del CFTR transfected cells and patient-derived F508delCFTR bronchiolar epithelia, without apparent cytopathology. These toxoids also increase glucocerobrosidase (GCC in N370SGCC Gaucher Disease fibroblasts (3x, another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases.

Lubricant Film Breakdown and Material Pick-Up in Sheet Forming of Advanced High Strength Steels and Stainless Steels when Using Environmental Friendly Lubricants

DEFF Research Database (Denmark)

Ceron, Ermanno; Olsson, M.; Bay, Niels

2014-01-01

chemically with the tool and workpiece material forming thin films, which adhere strongly to the surfaces and reduce the tendency to metal-metal contact and material pick-up. Production tests of new, environmentally benign tribo-systems are, however, costly and laboratory tests are preferred as a preliminary...... the tribological performance, i.e. tendency to material pick-up and galling, of the evaluated tribo-systems. Moreover the SEM analysis shows that different workpiece materials result in different types of material pick-up....

An analysis of the first-arrival times picked on the DSS and wide-angle seismic section recorded in Italy since 1968

Directory of Open Access Journals (Sweden)

R. Tondi

2004-06-01

Full Text Available We performed an analysis of refraction data recorded in Italy since 1968 in the frame of the numerous deep seismic sounding and wide-angle reflection/refraction projects. The aims of this study are to construct a parametric database including the recording geometric information relative to each profile, the phase pickings and the results of some kinematic analyses performed on the data, and to define a reference 1D velocity model for the Italian territory from all the available refraction data. As concerns the first goal, for each seismic section we picked the P-wave first-arrival-times, evaluated the uncertainties of the arrival-times pickings and determined from each travel time-offset curve the 1D velocity model. The study was performed on 419 seismic sections. Picking was carried out manually by an algorithm which includes the computation of three picking functions and the picking- error estimation. For each of the travel time-offset curves a 1D velocity model has been calculated. Actually, the 1D velocity-depth functions were estimated in three different ways which assume: a constant velocitygradient model, a varying velocity-gradient model and a layered model. As regards the second objective of this work, a mean 1D velocity model for the Italian crust was defined and compared with those used for earthquake hypocentre locations and seismic tomographic studies by different institutions operating in the Italian area, to assess the significance of the model obtained. This model can be used in future works as input for a next joint tomographic inversion of active and passive seismic data.

An order batching algorithm for wave picking in a parallel-aisle warehouse

NARCIS (Netherlands)

Gademann, A.J.R.M.; Berg, van den J.P.; Hoff, van der H.H.

2001-01-01

In this paper we address the problem of batching orders in a parallel-aisle warehouse, with the objective to minimize the maximum lead time of any of the batches. This is a typical objective for a wave picking operation. Many heuristics have been suggested to solve order batching problems. We

Pick-a-mood; development and application of a pictorial mood-reporting instrument

NARCIS (Netherlands)

Desmet, P.M.A.; Vastenburg, M.H.; Van Bel, D.; Romero Herrera, N.A.

2012-01-01

This paper presents ‘Pick-A-Mood’ (PAM), a cartoon-based pictorial instrument for reporting and expressing moods. The use of cartoon characters enables people to unambiguously and visually express or report their mood in a rich and easy-to-use way. PAM consists of three characters that each express

Association between Precipitation and Diarrheal Disease in Mozambique.

Science.gov (United States)

Horn, Lindsay M; Hajat, Anjum; Sheppard, Lianne; Quinn, Colin; Colborn, James; Zermoglio, Maria Fernanda; Gudo, Eduardo S; Marrufo, Tatiana; Ebi, Kristie L

2018-04-10

Diarrheal diseases are a leading cause of morbidity and mortality in Africa. Although research documents the magnitude and pattern of diarrheal diseases are associated with weather in particular locations, there is limited quantification of this association in sub-Saharan Africa and no studies conducted in Mozambique. Our study aimed to determine whether variation in diarrheal disease was associated with precipitation in Mozambique. In secondary analyses we investigated the associations between temperature and diarrheal disease. We obtained weekly time series data for weather and diarrheal disease aggregated at the administrative district level for 1997-2014. Weather data include modeled estimates of precipitation and temperature. Diarrheal disease counts are confirmed clinical episodes reported to the Mozambique Ministry of Health ( n = 7,315,738). We estimated the association between disease counts and precipitation, defined as the number of wet days (precipitation > 1 mm) per week, for the entire country and for Mozambique's four regions. We conducted time series regression analyses using an unconstrained distributed lag Poisson model adjusted for time, maximum temperature, and district. Temperature was similarly estimated with adjusted covariates. Using a four-week lag, chosen a priori, precipitation was associated with diarrheal disease. One additional wet day per week was associated with a 1.86% (95% CI: 1.05-2.67%), 1.37% (95% CI: 0.70-2.04%), 2.09% (95% CI: 1.01-3.18%), and 0.63% (95% CI: 0.11-1.14%) increase in diarrheal disease in Mozambique's northern, central, southern, and coastal regions, respectively. Our study indicates a strong association between diarrheal disease and precipitation. Diarrheal disease prevention efforts should target areas forecast to experience increased rainfall. The burden of diarrheal disease may increase with increased precipitation associated with climate change, unless additional health system interventions are undertaken.

Semantics based approach for analyzing disease-target associations.

Science.gov (United States)

Kaalia, Rama; Ghosh, Indira

2016-08-01

A complex disease is caused by heterogeneous biological interactions between genes and their products along with the influence of environmental factors. There have been many attempts for understanding the cause of these diseases using experimental, statistical and computational methods. In the present work the objective is to address the challenge of representation and integration of information from heterogeneous biomedical aspects of a complex disease using semantics based approach. Semantic web technology is used to design Disease Association Ontology (DAO-db) for representation and integration of disease associated information with diabetes as the case study. The functional associations of disease genes are integrated using RDF graphs of DAO-db. Three semantic web based scoring algorithms (PageRank, HITS (Hyperlink Induced Topic Search) and HITS with semantic weights) are used to score the gene nodes on the basis of their functional interactions in the graph. Disease Association Ontology for Diabetes (DAO-db) provides a standard ontology-driven platform for describing genes, proteins, pathways involved in diabetes and for integrating functional associations from various interaction levels (gene-disease, gene-pathway, gene-function, gene-cellular component and protein-protein interactions). An automatic instance loader module is also developed in present work that helps in adding instances to DAO-db on a large scale. Our ontology provides a framework for querying and analyzing the disease associated information in the form of RDF graphs. The above developed methodology is used to predict novel potential targets involved in diabetes disease from the long list of loose (statistically associated) gene-disease associations. Copyright © 2016 Elsevier Inc. All rights reserved.

Association between periodontal disease and cardiovascular disease

International Nuclear Information System (INIS)

Rehman, M.M.; Salama, R.P.

2004-01-01

Studies have supported the notion that subjects with periodontitis and patients with multiple tooth extractions as a result of chronic advanced periodontal disease (PDD) have a greater risk of developing Cardiovascular disease (CVD) than those who had little or no periodontal infection. Periodontitis may predispose affected patients to CVD by elevating systemic C-reactive protein level and pro-inflammatory activity in atherosclerotic lesions and accelerate development of cardiovascular diseases, Oral health variables including loss of teeth, positive plaque Benzoyl-D-L-Arginine- Naphthyl Amide test (BANA) scores, and compliant of xerostomia may by considered as risk indicators for CVD. Exact mechanism which links PDD and CVD has not been firmly established. The link between PDD and CVD may be attributed to bacteria entering blood stream and attaching to the fatty plaque in coronary artery and contributing to clot formation which can lead to heart attack. Inflammation caused by PDD increases the plaque build up. The association between the two disease entities is cause for concern. However, dental and medical practitioners should be aware of these findings to move intelligently to interact with inquiring patients with periodontitis. They should be urged to maintain medical surveillance of their cardiovascular status, and work on controlling or reducing all known risk factors associated with CVD, including periodontal infection. (author)

Association between periodontal disease and cardiovascular disease

Energy Technology Data Exchange (ETDEWEB)

Rehman, M M; Salama, R P [Ajman Univ. of Science and Technology Network, Abu-Dhabi Campus (United Arab Emirates)

2004-06-01

Studies have supported the notion that subjects with periodontitis and patients with multiple tooth extractions as a result of chronic advanced periodontal disease (PDD) have a greater risk of developing Cardiovascular disease (CVD) than those who had little or no periodontal infection. Periodontitis may predispose affected patients to CVD by elevating systemic C-reactive protein level and pro-inflammatory activity in atherosclerotic lesions and accelerate development of cardiovascular diseases, Oral health variables including loss of teeth, positive plaque Benzoyl-D-L-Arginine- Naphthyl Amide test (BANA) scores, and compliant of xerostomia may by considered as risk indicators for CVD. Exact mechanism which links PDD and CVD has not been firmly established. The link between PDD and CVD may be attributed to bacteria entering blood stream and attaching to the fatty plaque in coronary artery and contributing to clot formation which can lead to heart attack. Inflammation caused by PDD increases the plaque build up. The association between the two disease entities is cause for concern. However, dental and medical practitioners should be aware of these findings to move intelligently to interact with inquiring patients with periodontitis. They should be urged to maintain medical surveillance of their cardiovascular status, and work on controlling or reducing all known risk factors associated with CVD, including periodontal infection. (author)

High-performance integrated pick-up circuit for SPAD arrays in time-correlated single photon counting

Science.gov (United States)

Acconcia, Giulia; Cominelli, Alessandro; Peronio, Pietro; Rech, Ivan; Ghioni, Massimo

2017-05-01

The analysis of optical signals by means of Single Photon Avalanche Diodes (SPADs) has been subject to a widespread interest in recent years. The development of multichannel high-performance Time Correlated Single Photon Counting (TCSPC) acquisition systems has undergone a fast trend. Concerning the detector performance, best in class results have been obtained resorting to custom technologies leading also to a strong dependence of the detector timing jitter from the threshold used to determine the onset of the photogenerated current flow. In this scenario, the avalanche current pick-up circuit plays a key role in determining the timing performance of the TCSPC acquisition system, especially with a large array of SPAD detectors because of electrical crosstalk issues. We developed a new current pick-up circuit based on a transimpedance amplifier structure able to extract the timing information from a 50-μm-diameter custom technology SPAD with a state-of-art timing jitter as low as 32ps and suitable to be exploited with SPAD arrays. In this paper we discuss the key features of this structure and we present a new version of the pick-up circuit that also provides quenching capabilities in order to minimize the number of interconnections required, an aspect that becomes more and more crucial in densely integrated systems.

Successful pregnancy and delivery in a patient with Niemaoh-Pick disease after liver transplantation: report of one case and literature review%尼曼匹克病肝移植术后成功妊娠分娩1例并文献复习

Institute of Scientific and Technical Information of China (English)

郝庆春; 曾强; 刘保旺; 滕亮; 窦剑

2017-01-01

Objective To summarize the clinical experience of patient diagnosed with Niemaoh-Pick disease being pregnant after liver transplantation. Methods Clinical data of one case of type B Niemaoh-Pick disease being pregnant after liver transplantation were retrospectively analyzed. Results The patient successfully underwent liver transplantation combined with splenic artery ligation on July 8, 2011. She was well recovered postoperatively. After surgery, she received conventional anti-rejection treatment, and gradually switched to use of tacrolimus at a dosage of 2.5 mg/d. The serum drug concentration was maintained at 2 ng/mL. In September 2015, she was successfully pregnant. On June 2, 2016, she delivered a male infant through cesarean section. She could breastfeed the infant in a low quantity early after delivery. Both the mother and infant were followed up until submission date. The mother was physically stable and the infant grew normally. Conclusions Patients diagnosed with Niemaoh-Pick disease can obtain favorable clinical outcomes of pregnancy and delivery after liver transplantation.%目的 总结尼曼匹克病肝移植患者术后妊娠的临床经验.方法 回顾性分析1例尼曼匹克病B型患者接受肝移植后成功妊娠分娩的临床资料.结果 该例患者于2011年7月8日行肝移植术,同时行脾动脉结扎,手术及术后恢复顺利,术后常规抗排斥治疗,后逐渐改为单用他克莫司,剂量2.5 mg/d,血药浓度维持在2 ng/mL.2015年9月该患者成功妊娠,于2016年6月2日行剖宫产分娩一男婴.分娩后短期内少量母乳喂养,产妇及新生儿随访至投稿日,母亲正常,婴儿生长发育正常.结论 尼曼匹克病患者肝移植术后妊娠分娩可取得良好结局.

Automated Trajectory Planner of Industrial Robot for Pick-and-Place Task

Directory of Open Access Journals (Sweden)

S. Saravana Perumaal

2013-02-01

Full Text Available Industrial robots, due to their great speed, precision and cost-effectiveness in repetitive tasks, now tend to be used in place of human workers in automated manufacturing systems. In particular, they perform the pick-and-place operation, a non-value-added activity which at the same time cannot be eliminated. Hence, minimum time is an important consideration for economic reasons in the trajectory planning system of the manipulator. The trajectory should also be smooth to handle parts precisely in applications such as semiconductor manufacturing, processing and handling of chemicals and medicines, and fluid and aerosol deposition. In this paper, an automated trajectory planner is proposed to determine a smooth, minimum-time and collision-free trajectory for the pick-and-place operations of a 6-DOF robotic manipulator in the presence of an obstacle. Subsequently, it also proposes an algorithm for the jerk-bounded Synchronized Trigonometric S-curve Trajectory (STST and the ‘forbidden-sphere’ technique to avoid the obstacle. The proposed planner is demonstrated with suitable examples and comparisons. The experiments show that the proposed planner is capable of providing a smoother trajectory than the cubic spline based trajectory.

EFFICACY OF CITALOPRAM IN TREATMENT OF PATHOLOGICAL SKIN PICKING, A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL

Directory of Open Access Journals (Sweden)

M Arbabi

2008-11-01

Full Text Available "nVarious studies suggest that selective serotonin reuptake inhibitors (SSRIs may be useful in treating pathological skin picking (PSP. This study sought to assess effectiveness of citalopram in comparison with placebo in treating PSP. Forty five individuals with PSP were recruited in a four-week, randomized clinical trial of citalopram (20 mg/day in comparison with placebo. Study measures assessing skin picking severity, mental health status, obsessive compulsive disorder and quality of life were given at baseline, weeks 2 and 4. PSP severity, general health status, obsession-compulsion severity and quality of life level were similar between two groups at baseline (P > 0.05. Treatment analyses revealed significant improvements in quality of life, general health status and obsession-compulsion severity in citalopram group compared to placebo group (P < 0.05. Mean PSP severity reduction in citalopram group was more than placebo group but this difference was not significant. Citalopram can improve general health status and quality of life in individuals with PSP but its effect on skin picking behavior doesn't differ significantly with placebo. Other trials with longer time are needed to determine the exact efficacy of citalopram on PSP

Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

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Kexin Zhao

2017-05-01

Full Text Available Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs by Niemann-Pick C1 (NPC1. However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.

Simulation model of a single-server order picking workstation using aggregate process times

NARCIS (Netherlands)

Andriansyah, R.; Etman, L.F.P.; Rooda, J.E.; Biles, W.E.; Saltelli, A.; Dini, C.

2009-01-01

In this paper we propose a simulation modeling approach based on aggregate process times for the performance analysis of order picking workstations in automated warehouses with first-in-first-out processing of orders. The aggregate process time distribution is calculated from tote arrival and

Ischaemic heart disease mortality and years of work in trucking industry workers.

Science.gov (United States)

Hart, Jaime E; Garshick, Eric; Smith, Thomas J; Davis, Mary E; Laden, Francine

2013-08-01

Evidence from general population-based studies and occupational cohorts has identified air pollution from mobile sources as a risk factor for cardiovascular disease. In a cohort of US trucking industry workers, with regular exposure to vehicle exhaust, the authors previously observed elevated standardised mortality ratios for ischaemic heart disease (IHD) compared with members of the general US population. Therefore, the authors examined the association of increasing years of work in jobs with vehicle exhaust exposure and IHD mortality within the cohort. The authors calculated years of work in eight job groups for 30,758 workers using work records from four nationwide companies. Proportional hazard regression was used to examine relationships between IHD mortality, 1985-2000, and employment duration in each job group. HRs for at least 1 year of work in each job were elevated for dockworkers, long haul drivers, pick-up and delivery drivers, combination workers, hostlers, and shop workers. There was a suggestion of an increased risk of IHD mortality with increasing years of work as a long haul driver, pick-up and delivery driver, combination worker, and dockworker. These results suggest an elevated risk of IHD mortality in workers with a previous history of regular exposure to vehicle exhaust.

Editor’s Pick: Non-Alcoholic Fatty Liver Disease – Changing the Prevalence of Liver Cancer?

Directory of Open Access Journals (Sweden)

Benedetta Campana

2015-01-01

Full Text Available Due to its increasing prevalence, exceeding 25% of the Western population, non-alcoholic fatty liver disease (NAFLD merits recognition as one of the most frequent chronic liver diseases (CLD and requires consideration of the associated disease-related complications and their consequences for the surveillance and treatment of patients and the socio-economy worldwide. Along with the increasing incidence of NAFLD-related cirrhosis and end-stage liver disease, the frequency of NAFLD-related hepatocellular carcinoma (HCC is rising and expected to surpass HCC related to chronic hepatitis C in the upcoming future. These epidemiologic changes will impact on the overall mortality of CLD and the requirement of organs for transplantation. Although the risk of HCC in NAFLD, similar to other CLD, is related to fibrosis (advanced fibrosis increases the risk of HCC 25-fold, there are reports suggesting a considerable rate of HCC also developing in simple hepatic steatosis. Moreover, HCC is nowadays the leading cause of obesity-related cancer mortality; cancers of other origin such as colorectal cancer are more prevalent in patients with NAFLD and obesity. The pathophysiology of HCC has mainly been studied in models of viral hepatitis. Given the expected raise in NAFLD-related HCC, a better understanding of the pathophysiology of carcinogenesis in NAFLD and obesity is desired in order to better define chemopreventive strategies. Here we review the epidemiology, aetiology, and pathogenesis of HCC on the background of NAFLD and deduce potential consequences for the management of patients in respect to the NAFLD epidemic.

Perancangan dan Proses Pembuatan Inner Door Panel Mobil Pick Up Multiguna

Directory of Open Access Journals (Sweden)

Bambang Prayogi

2014-09-01

Full Text Available Sejak tahun 2012 Jurusan Teknik Mesin bekerja sama dengan PT. INKA mengembangkan mobil murah multigna. Mobil pick up tersebut diberi nama GEA. Pengembangan dilakukan pada body, chasis dan engine. Sebagai bagian dari body, pintu mobil juga akan dikembangkan. Pada tahun 2013, penelitian terhadap posisi handle pengatur kaca jendela atau window regulator mobil pick up GEA telah dilakukan. Evaluasi tersebut mengharuskan adanya perubahan desain dari inner door panel. Suatu rancangan pengembangan desain inner door panel perlu dilakukan agar inner door panel dapat diproduksi secara massal. Langkah-langkah penelitian yang dilakukan meliputi penyusunan list of requirement untuk pengembangan konsep, analisa getaran dan tegangan yang terjadi pada panel dengan bantuan software CATIA. Selanjutnya perancangan proses pembuatan dan perancangan punch and dies-nya dilakukan. Dari analisa getaran yang dilakukan, dapat diketahui inner door panel memiliki frekuensi natural sebesar 166,94 Hz (10.016,4 rpm artinya panel aman dan tidak terpengaruh oleh getaran dari mesin mobil. Tegangan yang terjadi pada inner door panel akibat gaya pembebanan pada handle pintu bagian dalam adalah 2,9159 x 107 Pa (2,97 Kg/mm2 sehingga lebih kecil dari tegangan ijin materialnya 13,94 Kg/mm2 dan rancangan masih berada dalam kategori aman. Untuk membuat inner door panel dilakukan 3 macam proses pembentukan yaitu trimming, embossing dan piercing. Total gaya pembentukan masing-masing proses sebagai berikut: Gaya pembentukan proses trimming = 48.96 ton, proses embossing = 26.89 ton dan proses piercing = 41.66 ton. Window regulator yang disarankan untuk digunakan pada mobil pick up multiguna ini adalah scissor type window regulator dengan tenaga penggerak manual. Pada perancangan punch and dies, tegangan kompresi masing-masing proses dihitung dan hasilnya adalah sebagai berikut: Tegangan kompresi proses trimming 0.11 Kg/mm2, tegangan kompresi proses embossing 0.28 Kg/mm2, tegangan kompresi

Association between periodontal disease and non-communicable diseases

Science.gov (United States)

Lee, Jae-Hong; Oh, Jin-Young; Youk, Tae-Mi; Jeong, Seong-Nyum; Kim, Young-Taek; Choi, Seong-Ho

2017-01-01

Abstract The National Health Insurance Service–Health Examinee Cohort during 2002 to 2013 was used to investigate the associations between periodontal disease (PD) and the following non-communicable diseases (NCDs): hypertension, diabetes mellitus, osteoporosis, cerebral infarction, angina pectoris, myocardial infarction, and obesity. Univariate and multivariate logistic regression analyses adjusting for potential confounders during the follow-up period—including age, sex, household income, insurance status, residence area, health status, and comorbidities—were used to estimated odds ratios (ORs) with 95% confidence intervals (CIs) in order to assess the associations between PD and NCDs. We enrolled 200,026 patients with PD and 154,824 subjects with a healthy oral status. Statistically, significant associations were found between PD and the investigated NCDs except for cerebral and myocardial infarction after adjusting for sociodemographic and comorbidity factors (P periodontitis pathogenesis as a triggering and mediating mechanism. PMID:28658175

Stirring, charging, and picking: hunting tactics of potamotrygonid rays in the upper Paraná River

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Domingos Garrone-Neto

Full Text Available Hunting tactics of potamotrygonid freshwater rays remain unreported under natural conditions. Three main foraging tactics of Potamotrygon falkneri and P. motoro are described here based on underwater observations in the upper Paraná River. Both species displayed similar behaviors. The most common tactic was to undulate the disc margins close to, or on, the bottom and thus stirring the substrate and uncovering hidden preys. Another tactic was to charge upon prey concentrated in the shallows. The least common tactic was to pick out prey adhered to the substrate. The first tactic is widespread in several species of marine rays in the Dasyatidae, whereas the remainder (especially picking up prey on substrata above water surface may be restricted to the Potamotrygonidae.

Comparison of magnetic and electrostatic Schottky pick-up in the CERN AD

CERN Document Server

Federmann, S

2013-01-01

The present note is intended to exploit the possibility of using a dedicated electrostatic beam pick-up for Schottky diagnostics in the future ELENA ring. A test setup is described allowing the evaluation of its performance compared to the extra low-noise beam current transformer used successfully in the AD. The results of this experiment are summarized and discussed.

Cholesterol Regulates Syntaxin 6 Trafficking at trans-Golgi Network Endosomal Boundaries

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Meritxell Reverter

2014-05-01

Full Text Available Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN. Here, using Chinese hamster ovary (CHO Niemann-Pick type C1 (NPC1 mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6 accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs. This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.

Pick-N-Pull Auto Dismantlers, Kansas City, LLC Inc. - Clean Water Act Public Notice

Science.gov (United States)

The EPA is providing notice of a proposed Administrative Penalty Assessment against Pick-N-Pull Auto Dismantlers, Kansas City, LLC, a subsidiary of Schnitzer Steel Industries, Inc., for alleged violations at its facilities at 8012 East Truman Rd., Kansas C

Associations of Systemic Diseases with Intermediate Uveitis.

Science.gov (United States)

Shoughy, Samir S; Kozak, Igor; Tabbara, Khalid F

2016-01-01

To determine the associations of systemic diseases with intermediate uveitis. The medical records of 50 consecutive cases with intermediate uveitis referred to The Eye Center in Riyadh, Saudi Arabia, were reviewed. Age- and sex-matched patients without uveitis served as controls. Patients had complete ophthalmic and medical examinations. There were 27 male and 23 female patients. Mean age was 29 years with a range of 5-62 years. Overall, 21 cases (42%) had systemic disorders associated with intermediate uveitis and 29 cases (58%) had no associated systemic disease. A total of 11 patients (22%) had asthma, 4 (8%) had multiple sclerosis, 3 (6%) had presumed ocular tuberculosis, 1 (2%) had inflammatory bowel disease, 1 (2%) had non-Hodgkin lymphoma and 1 (2%) had sarcoidosis. Evidence of systemic disease was found in 50 (5%) of the 1,000 control subjects. Bronchial asthma was found in 37 patients (3.7 %), multiple sclerosis in 9 patients (0.9%), inflammatory bowel disease in 3 patients (0.3%), and tuberculosis in 1 patient (0.1%). None of the control patients had sarcoidosis or lymphoma. There were statistically significant associations between intermediate uveitis and bronchial asthma (p = 0.0001), multiple sclerosis (p = 0.003) and tuberculosis (p = 0.0005). Bronchial asthma and multiple sclerosis were the most frequently encountered systemic diseases associated with intermediate uveitis in our patient population. Patients with intermediate uveitis should undergo careful history-taking and investigations to rule out associated systemic illness.

Grave's disease associated with immunoglobulin A nephropathy: A rare association.

Science.gov (United States)

Khan, I; Bhat, R A; Khan, I; Hameed, I

2015-01-01

Immunoglobulin A (Ig A) nephropathy is the most common form of primary glomerulonephritis. The association of Ig A nephropathy with Grave's disease has not been reported so far. We report a case of 20-year-old female with Grave's disease who presented with edema, facial puffiness, and decreased urine output. She was found to be hypertensive with renal failure and nephrotic range proteinuria. Renal biopsy revealed features of Ig A nephropathy. The patient was treated with oral corticosteroids (1 mg/kg/day). To our knowledge, this is the first case showing association of Grave's disease with Ig A nephropathy.

Automatic traveltime picking using local time-frequency maps

KAUST Repository

Saragiotis, Christos

2011-01-01

The arrival times of distinct and sufficiently concentrated signals can be computed using Fourier transforms. In real seis- mograms, however, signals are far from distinct. We use local time-frequency maps of the seismograms and its frequency derivatives to obtain frequency-dependent (instantaneous) traveltimes. A smooth division is utilized to control the resolution of the instantaneous traveltimes to allow for a trade-off between resolution and stability. We average these traveltimes over the frequency band which is data-dependent. The resulting traveltime attribute is used to isolate different signals in seismic traces. We demonstrate the effectiveness of this automatic method for picking arrivals by applying it on synthetic and real data. © 2011 Society of Exploration Geophysicists.

Abnormal brain activation in excoriation (skin-picking) disorder

DEFF Research Database (Denmark)

Odlaug, Brian L.; Hampshire, Adam; Chamberlain, Samuel R

2016-01-01

Background: Excoriation (skin-picking) disorder (SPD) is a relatively common psychiatric condition whose neurobiological basis is unknown. Aims: To probe the function of fronto-striatal circuitry in SPD. Method: Eighteen participants with SPD and 15 matched healthy controls undertook an executive...... encompassing bilateral dorsal striatum (maximal in right caudate), bilateral anterior cingulate and right medial frontal regions. These abnormalities were, for the most part, outside the dorsal planning network typically activated by executive planning tasks. Conclusions: Abnormalities of neural regions...... involved in habit formation, action monitoring and inhibition appear involved in the pathophysiology of SPD. Implications exist for understanding the basis of excessive grooming and the relationship of SPD with putative obsessive-compulsive spectrum disorders....

Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.

Science.gov (United States)

Sezgin, Erdinc; Azbazdar, Yagmur; Ng, Xue W; Teh, Cathleen; Simons, Kai; Weidinger, Gilbert; Wohland, Thorsten; Eggeling, Christian; Ozhan, Gunes

2017-08-01

While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/β-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity. © 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Trinary Associative Memory Would Recognize Machine Parts

Science.gov (United States)

Liu, Hua-Kuang; Awwal, Abdul Ahad S.; Karim, Mohammad A.

1991-01-01

Trinary associative memory combines merits and overcomes major deficiencies of unipolar and bipolar logics by combining them in three-valued logic that reverts to unipolar or bipolar binary selectively, as needed to perform specific tasks. Advantage of associative memory: one obtains access to all parts of it simultaneously on basis of content, rather than address, of data. Consequently, used to exploit fully parallelism and speed of optical computing.

Histopathological lesions associated with equine periodontal disease.

Science.gov (United States)

Cox, Alistair; Dixon, Padraic; Smith, Sionagh

2012-12-01

Equine periodontal disease (EPD) is a common and painful condition, the aetiology and pathology of which are poorly understood. To characterise the histopathological lesions associated with EPD, the skulls of 22 horses were assessed grossly for the presence of periodontal disease, and a standard set of interdental tissues taken from each for histopathological examination. Histological features of EPD included ulceration and neutrophilic inflammation of the gingival epithelium. Mononuclear and eosinophilic inflammation of the gingival lamina propria and submucosa was commonly present irrespective of the presence or degree of periodontal disease. Gingival hyperplasia was present to some degree in all horses, and was only weakly associated with the degree of periodontal disease. In all horses dental plaque was present at the majority of sites examined and was often associated with histological evidence of peripheral cemental erosion. Bacteria (including spirochaetes in four horses) were identified in gingival samples by Gram and silver impregnation techniques and were significantly associated with the presence of periodontal disease. This is the first study to describe histological features of EPD, and the first to identify associated spirochaetes in some cases. Histological features were variable, and there was considerable overlap of some features between the normal and diseased gingiva. Further investigation into the potential role of bacteria in the pathogenesis and progression of EPD is warranted. Copyright © 2012 Elsevier Ltd. All rights reserved.

The assessment of muscle strain with surface electromyograms during simulated mushroom picking

DEFF Research Database (Denmark)

Ohashi, Jun-Ya; Blangsted, Anne Katrine; Kofoed Nielsen, Pernille B.

2008-01-01

Muscle strain was assessed with surface EMG during simulated mushroom picking. Nine female subjects performed five periods of work (W1-W5). The duration of each period was about 20 min. W1, W2 and W3 were separated by a short break of several minutes. W3, W4 and W5 were separated by a rest period...

Embodied intersubjective engagement in mother-infant tactile communication: a cross-cultural study of Japanese and Scottish mother-infant behaviors during infant pick-up.

Science.gov (United States)

Negayama, Koichi; Delafield-Butt, Jonathan T; Momose, Keiko; Ishijima, Konomi; Kawahara, Noriko; Lux, Erin J; Murphy, Andrew; Kaliarntas, Konstantinos

2015-01-01

This study examines the early development of cultural differences in a simple, embodied, and intersubjective engagement between mothers putting down, picking up, and carrying their infants between Japan and Scotland. Eleven Japanese and ten Scottish mothers with their 6- and then 9-month-old infants participated. Video and motion analyses were employed to measure motor patterns of the mothers' approach to their infants, as well as their infants' collaborative responses during put-down, pick-up, and carry phases. Japanese and Scottish mothers approached their infants with different styles and their infants responded differently to the short duration of separation during the trial. A greeting-like behavior of the arms and hands was prevalent in the Scottish mothers' approach, but not in the Japanese mothers' approach. Japanese mothers typically kneeled before making the final reach to pick-up their children, giving a closer, apparently gentler final approach of the torso than Scottish mothers, who bent at the waist with larger movements of the torso. Measures of the gap closure between the mothers' hands to their infants' heads revealed variably longer duration and distance gap closures with greater velocity by the Scottish mothers than by the Japanese mothers. Further, the sequence of Japanese mothers' body actions on approach, contact, pick-up, and hold was more coordinated at 6 months than at 9 months. Scottish mothers were generally more variable on approach. Measures of infant participation and expressivity indicate more active participation in the negotiation during the separation and pick-up phases by Scottish infants. Thus, this paper demonstrates a culturally different onset of development of joint attention in pick-up. These differences reflect cultures of everyday interaction.

Embodied intersubjective engagement in mother–infant tactile communication: a cross-cultural study of Japanese and Scottish mother–infant behaviors during infant pick-up

Science.gov (United States)

Negayama, Koichi; Delafield-Butt, Jonathan T.; Momose, Keiko; Ishijima, Konomi; Kawahara, Noriko; Lux, Erin J.; Murphy, Andrew; Kaliarntas, Konstantinos

2015-01-01

This study examines the early development of cultural differences in a simple, embodied, and intersubjective engagement between mothers putting down, picking up, and carrying their infants between Japan and Scotland. Eleven Japanese and ten Scottish mothers with their 6- and then 9-month-old infants participated. Video and motion analyses were employed to measure motor patterns of the mothers’ approach to their infants, as well as their infants’ collaborative responses during put-down, pick-up, and carry phases. Japanese and Scottish mothers approached their infants with different styles and their infants responded differently to the short duration of separation during the trial. A greeting-like behavior of the arms and hands was prevalent in the Scottish mothers’ approach, but not in the Japanese mothers’ approach. Japanese mothers typically kneeled before making the final reach to pick-up their children, giving a closer, apparently gentler final approach of the torso than Scottish mothers, who bent at the waist with larger movements of the torso. Measures of the gap closure between the mothers’ hands to their infants’ heads revealed variably longer duration and distance gap closures with greater velocity by the Scottish mothers than by the Japanese mothers. Further, the sequence of Japanese mothers’ body actions on approach, contact, pick-up, and hold was more coordinated at 6 months than at 9 months. Scottish mothers were generally more variable on approach. Measures of infant participation and expressivity indicate more active participation in the negotiation during the separation and pick-up phases by Scottish infants. Thus, this paper demonstrates a culturally different onset of development of joint attention in pick-up. These differences reflect cultures of everyday interaction. PMID:25774139

An interactive tool for CT volume rendering and sagittal plane-picking of the prostate for radiotherapy treatment planning

International Nuclear Information System (INIS)

Jani, Ashesh B.; Pelizzari, Charles A.; Chen, George T.Y.; Grzezcszuk, Robert P.; Vijayakumar, Srinivasan

1997-01-01

Objective: Accurate and precise target volume and critical structure definition is a basic necessity in radiotherapy. The prostate, particularly the apex (an important potential site of recurrence in prostate cancer patients), is a challenging structure to define using any modality, including conventional axial CT. Invasive or expensive techniques, such as retrograde urethrography or MRI, could be avoided if localization of the prostate were possible using information already available on the planning CT. Our primary objective was to build a software tool to determine whether volume rendering and sagittal plane-picking, which are CT-based, noninvasive visualization techniques, were of utility in radiotherapy treatment planning for the prostate. Methods: Using AVS (Application Visualization System) on a Silicon Graphics Indigo 2 High Impact workstation, we have developed a tool that enables the clinician to efficiently navigate a CT volume and to use volume rendering and sagittal plane-picking to better define structures at any anatomic site. We applied the tool to the specific example of the prostate to compare the two visualization techniques with the current standard of axial CT. The prostate was defined on 80-slice CT scans (scanning thickness 4mm, pixel size 2mm x 2mm) of prostate cancer patients using axial CT images, volume-rendered CT images, and sagittal plane-picked images. Results: The navigation of the prostate using the different visualization techniques qualitatively demonstrated that the sagittal plane-picked images, and even more so the volume-rendered images, revealed the prostate (particularly the lower border) better in relationship to the surrounding regional anatomy (bladder, rectum, pelvis, and penile structures) than did the axial images. A quantitative comparison of the target volumes obtained by navigating using the different visualization techniques demonstrated that, when compared to the prostate volume defined on axial CT, a larger volume

Parametric Optimal Design of a Parallel Schönflies-Motion Robot under Pick-And-Place Trajectory Constraints

DEFF Research Database (Denmark)

Wu, Guanglei; Bai, Shaoping; Hjørnet, Preben

2015-01-01

This paper deals with the parametric optimum design of a parallel Schoenflies-motion robot, named "Ragnar", designed for fast and flexible pick-and-place applications. The robot architecture admits a rectangular workspace, which can utilize the shop-floor space efficiently. In this work......, the parametric models of the transmission quality, elasto-statics and dynamics are established. By taking into consideration of design requirements and pick-and-place trajectory, a comprehensive multi-objective optimization problem is formulated to optimize both kinematic and dynamic performances. The Pareto......-front is obtained, which provides optimal solutions to the robot design. Robot prototyping work based on the optimal results is described....

Trichotillomania (hair pulling disorder), skin picking disorder, and stereotypic movement disorder: toward DSM-V.

Science.gov (United States)

Stein, Dan J; Grant, Jon E; Franklin, Martin E; Keuthen, Nancy; Lochner, Christine; Singer, Harvey S; Woods, Douglas W

2010-06-01

In DSM-IV-TR, trichotillomania (TTM) is classified as an impulse control disorder (not classified elsewhere), skin picking lacks its own diagnostic category (but might be diagnosed as an impulse control disorder not otherwise specified), and stereotypic movement disorder is classified as a disorder usually first diagnosed in infancy, childhood, or adolescence. ICD-10 classifies TTM as a habit and impulse disorder, and includes stereotyped movement disorders in a section on other behavioral and emotional disorders with onset usually occurring in childhood and adolescence. This article provides a focused review of nosological issues relevant to DSM-V, given recent empirical findings. This review presents a number of options and preliminary recommendations to be considered for DSM-V: (1) Although TTM fits optimally into a category of body-focused repetitive behavioral disorders, in a nosology comprised of relatively few major categories it fits best within a category of motoric obsessive-compulsive spectrum disorders, (2) available evidence does not support continuing to include (current) diagnostic criteria B and C for TTM in DSM-V, (3) the text for TTM should be updated to describe subtypes and forms of hair pulling, (4) there are persuasive reasons for referring to TTM as "hair pulling disorder (trichotillomania)," (5) diagnostic criteria for skin picking disorder should be included in DSM-V or in DSM-Vs Appendix of Criteria Sets Provided for Further Study, and (6) the diagnostic criteria for stereotypic movement disorder should be clarified and simplified, bringing them in line with those for hair pulling and skin picking disorder. (c) 2010 Wiley-Liss, Inc.

Hydrated disease of bone

International Nuclear Information System (INIS)

Mishwani, A.H.; Ahmed, M.; Anwar, S.D.

2003-01-01

A case of primary hydatid disease of the right femur is reported that presented with pathological fracture and was diagnosed at the time of exploration for biopsy. The patient was treated by removal of all cysts, irrigation with colloidal solution, bone grafting and immobilization of the fracture followed by four cycles of oral Albendazole. Eosinophilia and serological tests reverted to normal but the patient died due to acute myocardial infarction six months later. This uncommon condition should be considered in the differential diagnosis of pathological fractures, bone pain or osteolytic lesions, especially in patients of rural and farmer background.(author)

Functional neuroimaging of Alzheimer's disease and other dementias

International Nuclear Information System (INIS)

Wang Ruimin

2001-01-01

Dementing illnesses comprise Alzheimer's disease (AD), Pick's disease, Multi-infarct dementia (MID) and other neurological disorders. These diseases have different clinical characters respectively. Neuropsychological examinations can help to diagnose and differential diagnose dementias. The development of neuroimaging dementias is more and more rapid. 18 F-FDG PET method shows neo-cortical hypometabolism occurring in the biparietal-temporal lobes and left-right asymmetry of AD patients in the early stage. It can also differential diagnose Ad from other dementias

Flow time prediction for a single-server order picking workstation using aggregate process times

NARCIS (Netherlands)

Andriansyah, R.; Etman, L.F.P.; Rooda, J.E.

2010-01-01

In this paper we propose a simulation modeling approach based on aggregate process times for the performance analysis of order picking workstations in automated warehouses. The aggregate process time distribution is calculated from tote arrival and departure times. We refer to the aggregate process

Association between colonic polyps and diverticular disease

Institute of Scientific and Technical Information of China (English)

Tetsuo Hirata; Yuko Kawakami; Nagisa Kinjo; Susumu Arakald; Tetsu Arakaki; Akira Hokama; Fukunori Kinjo; Jim Fujita

2008-01-01

AIM: TO evaluate the association between colonic polyps and diverticular disease in Japan.METHODS: We retrospectively reviewed the medical records of 672 consecutive patients who underwent total colonoscopy between August 2006 and April 2007 at Nishinjo Hospital, Okinawa, Japan. Patients with ahistory of any of the following were excluded from the study: previous polypectomy, colonic resection, and inflammatory bowel diseases. The association between colonic polyps and diverticular disease was analyzed by logistic regression analysis, adjusted for age and sex.RESULTS: Prevalence of colonic polyps in all patients with diverticular disease was significantly higher than that in those without diverticular disease (adjusted odds ratio 1.7).CONCLUSION: Our data showed that patients with diverticular disease have a higher risk of colonic polyps compared to those without.

TREATMENT OF CLOSTRIDIUM DIFFICILE- ASSOCIATED DISEASE

Directory of Open Access Journals (Sweden)

Snezana Antic-Mladenovic

2007-04-01

Full Text Available Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacillus that is widely distributed in the environment, but is found as a part of a normal large bowel flora in approximately 3% of normal adults. C. difficile produces two protein exotoxins: toxin A and toxin B. Both toxins are responsible for causing the sings and symptoms of disease.C. difficile is now thought to be responsible for a spectrum of diseases, ranging from asymptomatic colonization to diarrhea of varying severity, life-threatening colitis, often as a consequence of long-term antibiotic exposure. This spectrum has become known as C. difficile-associated disease (CDAD.Treatment of Clostridium difficile-associated disease demand administration of effi-cient antibiotics (vancomycin, metronidazole, anion exchange resins and probiotics (Lactobacillus spp., Saccharomyces boulardii.

An automated framework for NMR resonance assignment through simultaneous slice picking and spin system forming

KAUST Repository

Abbas, Ahmed; Guo, Xianrong; Jing, Bingyi; Gao, Xin

2014-01-01

positives and negatives impair the performance of resonance assignment methods. One of the main reasons for this problem is that the computational research community often considers peak picking and resonance assignment to be two separate problems, whereas

Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

Science.gov (United States)

Barrett, Matthew J; Koeppel, Alexander F; Flanigan, Joseph L; Turner, Stephen D; Worrall, Bradford B

2016-01-01

Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE  70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.

What Skills and Tactics Are Needed to Play Adult Pick-Up Basketball Games?

Science.gov (United States)

Wang, Jianyu; Liu, Wenhao; Moffit, Jeffrey

2010-01-01

The purpose of this study was to examine skill levels and performance patterns of regular players of pick-up basketball games. By a survey, 65 participants were identified as regular players and participated in the study. An observational instrument used to analyze game performance of the participants was developed and both content and construct…

Prevalence of periodontal disease, its association with systemic diseases and prevention

OpenAIRE

Nazir, Muhammad Ashraf

2017-01-01

Periodontal diseases are prevalent both in developed and developing countries and affect about 20-50% of global population. High prevalence of periodontal disease in adolescents, adults, and older individuals makes it a public health concern. Several risk factors such as smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to periodontal diseases. Robust evidence shows the association of periodontal diseases with systemic diseases such as cardiovascular di...

Periodontal disease severity is associated with micronutrient intake.

Science.gov (United States)

Luo, P-P; Xu, H-S; Chen, Y-W; Wu, S-P

2018-03-06

This study aimed to examine if specific micronutrients were associated with periodontal disease using data from the US National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. Participants who were aged 30 years or more and received complete periodontal examinations were included. Regression analyses were performed to determine associations of variables of interest with periodontal disease. Data of 6415 NHANES participants were included in the analysis. Multivariable analysis revealed that less intake of vitamin A (adjusted odds ratio (aOR) = 1.784), vitamin B1 (aOR = 1.334), vitamin C (aOR = 1.401), vitamin E (aOR = 1.576), iron (aOR = 1.234), folate (aOR = 1.254) and phosphorus (aOR = 1.280) was associated with increased severity of periodontal disease. Compared with the highest level of vitamin D intake, the second highest level of vitamin D intake was associated with lower severity of periodontal disease (aOR = 0.727). Insufficient intake of vitamin A, B1, C and E, iron, folate and phosphorus was significantly associated with severity of periodontal disease. Results of the present study suggest that the above micronutrients may be increased in the diet or taken as dietary supplements in order to reduce severity of periodontal disease. © 2018 Australian Dental Association.

Frontotemporal Dementia (Pick's Disease)

Science.gov (United States)

... changes in food preferences; agitation or, conversely, blunted emotions; neglect of personal hygiene; repetitive or compulsive behavior, and decreased energy and motivation. The second type primarily features symptoms of language ...

Whole body organization during a symmetric bimanual pick up task in overweight and obese children.

Science.gov (United States)

Hung, Ya-Ching; Mangiafreno, Melissa; Gill, Simone V

2017-02-01

Information on the effects of obesity on the biomechanics of whole body movement control in children is limited. The purpose of the current study is to test the hypothesis that during a simple pick up task, overweight and obese children will organize their whole body movements differently than those in normal weight children. Twelve children who were overweight or obese (5-13 years old) and twelve age matched normal weight children participated in the study. Children picked up an empty box to waist height at a self-selected pace while kinematic and kinetic data were recorded and analyzed using a VICON system and two AMTI force plates. The overweight and obese group showed less knee flexion in both legs, more spine flexion, and less excursion in the height of their center of mass (all Psoverweight and obese group had more anterior movement in their center of mass (Poverweight and obese group had greater anterior excursion with faster average anterior moving speed and spent a longer time with the center of pressure reached forward (all Psoverweight and obese children organize their whole body movement during a simple pick up task differently with higher and more forward center of mass, quickly shifting their center of pressure anteriorly, and with a longer period of time with the center of pressure remaining forward. Their movement strategy may put them in a less stable condition and thus make them prone to losing balance. Copyright © 2016 Elsevier B.V. All rights reserved.